Brain TRPV1 channel-mediated calcium influx: the immunomodulatory pathway of acupuncture in neuroinflammation

Neuroinflammation represents the central pathological process in neurological disorders. Effectively regulating neuroinflammation to restore immune homeostasis and alleviate neuronal damage has emerged as a critical strategy in the prevention and treatment of these diseases. In recent years, the role of acupuncture in neuroimmune regulation, along with its anti-inflammatory and analgesic effects, has attracted considerable attention. Its potential to modulate immune homeostasis and inflammatory responses through various targets and pathways has been gradually elucidated, offering new research directions for the regulation of neuroinflammation. A series of studies have emphasized that acupuncture has significant clinical applications by regulating the immunoinflammatory pathway mediated by the brain’s TRPV1 channel. This discovery not only enhances the scientific understanding of the mechanisms underlying acupuncture but also offers new potential targets for the prevention and treatment of neuroinflammation-related diseases. The immunomodulatory properties of brain TRPV1 channels in inflammation associated with the nervous system have been emphasized. Furthermore, this study explores the immunomodulatory benefits of acupuncture in treating neuroinflammation, focusing on the potential mechanisms of TRPV1 channels at the brain level, as well as the criteria for selecting acupoints, intensity, frequency, and other relevant parameters in these studies. A deeper understanding of the neuroimmune regulatory mechanisms mediated by brain TRPV1 channels may offer new strategies and approaches for developing treatments or preventing neuropathological diseases.

1 Introduction

Neuroinflammation is a specific immune response of the central nervous system (CNS) to injury, infection, or pathological stimuli. Moderate inflammatory responses can exert protective effects by eliminating pathogens, phagocytosing cellular debris, and maintaining microenvironmental homeostasis. However, excessive or persistent neuroinflammation can lead to immune hyperactivation in the CNS, further damaging the brain and causing pathological alterations in brain structure and function. It is characterized by the abnormal activation of microglia and astrocytes, a cascade release of pro-inflammatory mediators, and the upregulation of neurotoxic pathways. The resulting chronic inflammatory microenvironment not only disrupts the blood-brain barrier (BBB) and promotes the infiltration of peripheral immune cells but also induces pathological changes such as mitochondrial dysfunction in brain neurons and synaptic plasticity impairment, leading to the malignant progression of diseases (1, 2). It is noteworthy that a significant degree of neuroinflammation is closely associated with damage to both the peripheral nervous system (PNS) and the CNS. Persistent neuroinflammation is a key factor in the pathogenesis of neurological disorders, driving disease progression and causing brain damage (3–5). Meanwhile, central sensitization, as a compensatory response of the nervous system to peripheral and central neural lesions, manifests as an overexcited state of the CNS. The nociceptive transmission signals it mediates can further activate the inflammatory cascade in the CNS, and the resulting neuroinflammatory response can exacerbate the pathological changes associated with central sensitization, ultimately leading to peripheral pain hypersensitivity in the corresponding spinal cord or brain regions, as well as the systemic spread of inflammation (6–10). The pathological interplay between neuroinflammation, neurological damage, and central sensitization, coupled with the crosstalk between peripheral and central immunity, forms a vicious cycle that exacerbates pathological alterations in the nervous system and leads to irreversible damage to the brain. This situation has emerged as a significant challenge in the global public health domain.

According to the 2021 Global Burden of Disease Study, neurological disorders have emerged as the leading cause of global disability and mortality over the past 30 years, encompassing conditions such as stroke, Alzheimer’s disease (AD), epilepsy (EP), Parkinson’s disease (PD), traumatic brain injury (TBI), multiple sclerosis (MS), spinal cord injury (SCI), and diabetic neuropathy (DN) (11, 12). Concurrently, diseases characterized by central sensitization as the core pathological mechanism, including fibromyalgia (FM), neuropathic pain (NP), and chronic fatigue syndrome (CFS), are emerging as significant challenges in both basic research and clinical translation due to their complex neuroimmune interaction mechanisms (13–16). Furthermore, numerous studies have demonstrated that the progression of neurological disorders and their associated central sensitization is often accompanied by brain function impairments, such as depression, anxiety, and cognitive deficits (10, 17–22). Neuroinflammation, a significant driver of these diseases, causes irreversible damage to the CNS, which is centered around the brain. 1his severely affects individuals’ quality of life and poses a substantial threat to society, thus emerging as a key mechanism in neuropathological diseases (23). Currently, there are no specific treatment options aimed at alleviating neuroinflammation, only symptomatic treatments are available. Moreover, due to the physiological and structural characteristics of the BBB, delivering drugs to the brain to prevent and treat neuroinflammatory lesions presents a significant challenge (24). Therefore, researching and developing non-pharmacological or non-invasive methods to establish a precise regulatory system targeting neuroimmune inflammatory damage has become an urgent need in translational medicine research.

In 2016, the National Institutes of Health (NIH) launched the “Stimulating Peripheral Activity to Relieve Conditions” (SPARC) program. This initiative aims to advance the development of novel peripheral nerve stimulation devices and modulation strategies by elucidating the anatomical and functional connectivity maps between peripheral nerves and target organs. Furthermore, it has offered new perspectives and insights for research on surface stimulation therapies, such as acupuncture (25–27). Current studies have reported that acupuncture therapy exerts significant anti-inflammatory and analgesic effects under various disease conditions by regulating neuroimmune mechanisms and related inflammatory pathways (28–31). Furthermore, it emphasizes a close biological association with the transient receptor potential vanilloid 1 (TRPV1) channel (32–36). As a pivotal nociceptor, the TRPV1 channel has had its molecular mechanisms mediating temperature and pain perception progressively elucidated since its initial identification in neurons in 1997, with related discoveries earning the Nobel Prize in Physiology or Medicine in 2021 (37, 38). Research over the past two decades has unveiled the central role of TRPV1 channels in NP and inflammatory diseases (39, 40), while confirming their critical function in transmitting acupuncture-induced cutaneous stimulation signals. Both peripheral and spinal TRPV1 channels can respond to acupuncture stimuli, mediating anti-inflammatory and analgesic effects through the activation of the autonomic nervous system (ANS) and modulation of neuroimmune interactions (33, 41). In addition to the expression of TRPV1 channels in peripheral tissues, organs, and the spinal cord, significant expression characteristics are also observed in various cell types and different regions of the brain (36, 42–45). TRPV1 channels in distinct brain areas initiate a series of immune inflammatory cascades by mediating Ca²⁺ influx in response to upstream noxious signals. This mechanism not only exacerbates the amplification of nociceptive signals but may also result in neuronal damage and dysfunction in the brain. However, compared to functional studies of TRPV1 channels in peripheral tissues and the spinal cord, there remains a gap in understanding its role within the brain. Although emerging evidence suggests that brain TRPV1 may participate in neuroinflammatory processes by regulating calcium signaling, its specific mechanisms of action and association with acupuncture modulation have yet to be elucidated.

This review will systematically explore the regulatory mechanisms of acupuncture on brain TRPV1 channels, with the aim of evaluating its immunomodulatory potential in neuroinflammatory-related diseases. The study intends to provide theoretical foundations for the development of TRPV1-targeted acupuncture therapies and to identify critical research directions that require breakthroughs in this field.

2 Literature retrieval and methods

2.1 Search strategy

This study primarily examines the mechanism by which acupuncture therapy regulates the TRPV1 channel in the brain, thereby mitigating the inflammatory response resulting from nervous system injuries. Consequently, various descriptions pertaining to “TRPV1” and “acupuncture” have been thoroughly considered. The search keyword combinations include “TRPV1/ransient Receptor Potential Vanilloid 1”, “acupuncture/acupoint/acupuncture point/meridian”, along with other relevant Chinese and English terms to ensure comprehensive retrieval of pertinent literature. Studies were sourced from PubMed, Web of Science, CNKI, and the Wanfang database, with literature selected for analysis spanning from the inception of these databases to August 30, 2025. Ultimately, a total of 22 relevant studies were chosen for analysis and review.

2.2 Inclusion criteria

The inclusion criteria are as follows: (1) Research Type: The study must be publicly published original experimental research, including cellular, animal, or clinical studies. Systematic reviews or meta-analyses may be referenced; (2) Subjects: Eligible subjects include cell models, neuroinflammatory animal models, or clinical patients; (3) Intervention Measures: Any form of acupuncture intervention is acceptable, including manual acupuncture(MA) and electroacupuncture(EA), with stimulation sites that may include acupoints or non-acupoints; (4) Control Measures: Control groups may consist of sham acupuncture groups, model control groups, or blank control groups; (5) Outcome Indicators: The study must measure outcome indicators related to the TRPV1 channel and neuroinflammatory markers either directly or indirectly.

2.3 Exclusion criteria

The exclusion criteria are as follows: (1) Non-peer-reviewed literature, such as conference abstracts, dissertations, reviews, and editorials; (2) Literature for which full text cannot be obtained or that contains incomplete data, or is unclear; (3) Literature that has been published repeatedly (if repeated, only the most complete data is included); (4) Research content that is not directly related to the ‘acupuncture-TRPV1-neuroinflammation’ pathway; (5) Studies that focus solely on the regulation of TRPV1 in neuroinflammation without involving acupuncture treatment.

2.4 Data extraction method

Two researchers independently extracted data using a pre-designed standardized data extraction table and conducted cross-checks to ensure accuracy. The extracted content primarily includes: (1) Basic information: first author, publication year, and journal; (2) Research characteristics: research type (in vivo/in vitro), animal or cell strain, and model establishment method; (3) Intervention details: acupuncture type, acupoint selection, and parameters (intensity, frequency, waveform, duration, and course of treatment); (4) Control settings: specific circumstances of the control group; (5) Core mechanism indicators: TRPV1 mRNA and protein expression levels, localization, use of TRPV1 antagonists or agonists, activation status of microglia and astrocytes, levels of pro-inflammatory and anti-inflammatory cytokines, and related signaling pathways (such as NF-κB and MAPK); (6) Main results and conclusions: the effect of acupuncture and the role of TRPV1 in this context.

3 The immunoregulatory pathway mediated by brain TRPV1 channels in neuroinflammation

As the center of neuro-immune regulation, the brain not only orchestrates the coordinated operation of the systemic immune response but also serves as the primary target area for the neuroinflammatory cascade. Neuroinflammation represents the central response mechanism of the CNS to pathological injury. This pathological process is characterized by the activation of glial cells, infiltration of immune cells, and a robust release of inflammatory factors, which together form a complex neuroimmune regulatory network within the brain (1). There exists a complex bidirectional regulatory relationship between neuroinflammation and neurological diseases (Figure 1). On one hand, nerve damage and central sensitization resulting from neurological lesions initiate an inflammatory cascade by activating central immune cells. When the nervous system is compromised, nociceptive conduction signals induced by peripheral nerve, spinal cord, and brain injuries evoke microglial phenotype reprogramming across various brain regions (Figure 1a). This process regulates gene transcription and the release of nociceptive mediators through oscillations in calcium signaling (46), thereby forming a complex neuroimmune interaction network with astrocytes, vascular endothelial cells, and infiltrating immune cells (such as T cells, granulocytes, and macrophages) (47, 48). This interaction activates nociceptive signaling pathways (49, 50), which drives the propagation of neuroinflammation. Conversely, the excessive production of reactive oxygen species (ROS), pro-inflammatory factors, and excitotoxic substances within the inflammatory microenvironment not only results in cellular damage and death, exacerbating the inflammatory response, but also facilitates the infiltration of peripheral immune cells and the migration of inflammatory mediators across the blood-brain barrier (BBB) by compromising its permeability. This creates a vicious cycle of ‘inflammatory damage-barrier destruction-excitation of inflammation that is challenging to interrupt (1, 51, 52), further worsening nerve damage and pathological alterations in the nervous system. Additionally, this process leads to abnormal synaptic plasticity and neuronal dysfunction in the brain (17–19, 51, 53) (Figure 1b). By impacting the functionality of the corresponding brain regions, it adversely affects the sensory, motor, emotional, and cognitive functions associated with these areas (1, 10, 17–21), ultimately contributing to disease progression (Figure 1c).

Figure 1

Figure 1. The bidirectional regulatory mechanisms between neuroinflammation and CNS lesions are complex and multifaceted. (a) Nociceptive signals, mediated by both peripheral and central neural pathologies, trigger neuroinflammatory responses in corresponding brain regions through a series of neural and molecular pathways. This process subsequently promotes glial cell activation across multiple brain areas, modulates the release of inflammatory mediators, and collaborates with immune cells such as T cells, neutrophils, and macrophages to drive the propagation of inflammation. (b) Within the pathological inflammatory microenvironment of the brain, the progressive accumulation of DAMPs, ROS, pro-inflammatory mediators, and Glu neurotoxic factors leads to cellular damage and disruption of the BBB. This disruption induces further infiltration of peripheral immune cells, exacerbating inflammatory responses and thereby forming a vicious cycle. (c) The persistently progressive neuroinflammatory response not only promotes the onset and progression of neurological disorders but also mediates peripheral sensitization and the generation of inflammatory pain, ultimately leading to sensory, movement, emotional and cognitive dysfunction in the brain. Created with Figdraw 2.0. (ID:WIYAY2baee).

Studies have demonstrated that the activation of TRPV1 channels and the subsequent influx of Ca²⁺ play a crucial role in various aspects of neuroinflammation. Under pathological conditions, nociceptive signals from both the PNS and CNS are integrated within distinct regions of the brain through multi-level neural networks, including the peripheral nerves, dorsal root ganglia, spinal cord, and brain. This integration forms a positive feedback loop with abnormal activities generated by central sensitization, leading to an imbalance in the microenvironment of the brain. This imbalance triggers the activation of TRPV1 channels, resulting in continuous calcium influx, which participates in the activation of immune cells, the transduction of inflammatory signaling pathways, the release of damage-associated molecular patterns (DAMPs), the maintenance of redox balance, and the disruption of synaptic plasticity, among other biochemical pathways. These different mechanisms interact with one another, contributing to a persistent and exacerbated neuroinflammatory response and cell loss, ultimately causing irreversible damage to the nervous system and brain function.

3.1 Basic characteristics and functions of TRPV1 channel

The transient receptor potential (TRP) cation channel superfamily encompasses a diverse group of ion channel proteins that are widely distributed across eukaryotic organisms. Among these, the TRPV1 channel is recognized as the first identified member of the transient receptor potential vanilloid (TRPV) subfamily in mammals. It is expressed not only in peripheral neurons, dorsal root ganglia (DRG), and the spinal cord, but also extensively in various brain regions, including the cortex, hippocampus (HPC), amygdala (AMY), thalamus (TH), midbrain periaqueductal gray (PAG), and cerebellum (CB). Furthermore, TRPV1 is found in neurons, microglia, astrocytes, and other glial cells (36, 42–45). The TRPV1 channel is a tetrameric protein composed of four identical subunits (Figure 2a). Each subunit consists of transmembrane domains, an intracellular N-terminus (TRPV1-N), and an intracellular C-terminus (TRPV1-C) (Figure 2b). These distinct structural domains possess corresponding functional characteristics, enabling the channel to play a crucial role in signaling transduction during physiological and pathological processes by responding to various chemical and physical stimuli (54–56). The transmembrane domain, an essential component of the gating mechanism, comprises six transmembrane helices. Among these, the S1-S4 transmembrane helices and the S4-S5 linker constitute conserved domains. The S5 helix, pore helix, and S6 helix collectively form a non-selective cation pore with high permeability to Ca²⁺, which regulates the entry of Ca²⁺ ions across the cell membrane in response to various stimuli (55, 57). This process mediates the inflammatory response by promoting glial cell activation and triggering a series of nociceptive pathways mediated by Ca²⁺/calmodulin-dependent protein kinase (CaMK), protein kinase A (PKA), and protein kinase C (PKC) (58–60) (Figure 2c). TRPV1-N consists of an ankyrin repeat domain (ARD), a linker domain, and a pre-S1 helix, which are closely associated with oxidative stress responses. Studies demonstrate that it can directly interact with Phosphatidylinositol 3-kinase (PI3K) to mediate inflammatory signaling (Figure 2d) (56, 61). TRPV1-C contains a TRP domain and β-sheet regions, capable of interacting with signaling proteins such as PKA and PKC, This interaction further enhances the expression of the TRPV1 channel and exacerbates Ca²⁺ influx (62, 63), and influences signal transduction pathways, including inflammatory responses, gene expression regulation, and pain perception (Figure 2e) (64–67).

Figure 2

Figure 2. The three-dimensional structure of TRPV1 channel. (a) The TRPV1 channel is homotetrameric. (b) The pattern of functional domain of TRPV1 channel in membrane. Each monomer of TRPV1 channel composed of an N-terminal, a C-terminal and a transmembrane domain (TMD) comprising six transmembrane helices (S1-S6). (c) Structural details of S5, the pore helix and S6. (d) Structural details of the pre-S1 helix, the linker domain and TRP domain. (e) The β-sheet region consists of the C-terminal and a structure before ARD the N-terminal. The 3D Structure of TRPV1 channel from Pubchem database (PDB code: 7mz5); (b) Created with Figdraw 2.0. (ID:YAIPP5535f).

Studies have demonstrated that the TRPV1 channel is responsive to pathological microenvironmental features, including low pH (pH < 5.9), thermal stimulation (temperatures exceeding 43 °C), infiltration of inflammatory mediators, accumulation of ROS, and stimulation by endogenous compounds such as capsaicin and cannabinoids. Through specific conformational activation, TRPV1 facilitates the transmembrane influx of cations, predominantly Ca²⁺, thereby mediating critical physiological and pathological processes. In the PNS, TRPV1 channels are predominantly expressed in the nerve terminals of primary afferent sensory neurons, which mainly consist of small- and medium-diameter neurons classified as nociceptors. When noxious stimuli act on these sensory nerve terminals, TRPV1 channels open, inducing cation influx that leads to depolarization of the nerve terminals and the generation of action potentials, thereby transmitting pain signals to the CNS, specifically the spinal cord. In the CNS, TRPV1 channels are highly concentrated in the spinal dorsal horn. Upon receiving nociceptive signals from peripheral afferents, these channels become activated, promoting Ca²⁺ influx, enhancing vesicle release, and increasing neurotransmitter secretion, which amplifies the transmission of pain signals. This process not only facilitates the formation of “central sensitization”, but also further propagates signals to higher centers of the brain. TRPV1 channels in various brain regions respond to upstream nociceptive signals, triggering a series of complex neuroimmune and biochemical cascade events mediated by Ca²⁺ influx. These events not only amplify the CNS’s processing of nociceptive signals but can also induce neuroinflammation, abnormal synaptic plasticity, and excitotoxic neuronal damage, ultimately leading to neuronal injury and impairment of brain neural functions. From the perspective of molecular mechanisms, the functional core of TRPV1 channels is centered on mediating Ca²⁺ influx. Activated TRPV1 channels primarily undergo dynamic conformational changes that create permeable pores, facilitating the entry of calcium ions and resulting in increased intracellular Ca²⁺ concentrations. This process constitutes a critical secondary messenger signal. The influx of Ca²⁺ directly initiates multi-level signal transduction pathways, including intracellular calcium oscillations, kinase phosphorylation cascades, and the activation of transcription factors. Ultimately, by regulating immune cell activity, neuro-immune interactions, the release of inflammatory mediators, and oxidative stress pathways, TRPV1 channels serve as a key molecular hub within the body’s immune regulatory network (68).

3.2 The immune regulation mediated by brain TRPV1 channels in neuroinflammation

The innate immune response triggered by neural injury activates immune cells, promotes the release of inflammatory factors, and initiates a series of complex cascade events that induce cellular damage and death, exacerbating the progression of inflammatory responses. Microglia and astrocytes are the primary glial cells involved in CNS inflammatory responses. Among these, microglia, which function as brain-resident macrophages, play a pivotal role in immune surveillance and the maintenance of brain homeostasis. They serve as crucial regulators of the brain’s innate immune response and are significant effector cells in neuroinflammation (69). Astrocytes, traditionally regarded as supportive cells for neurons, provide metabolic support, mediate neurovascular coupling, and regulate blood-brain barrier (BBB) permeability (47). Microglia, the primary immune cells in the CNS, play a pivotal role in driving the neuroinflammatory cascade (70), Research has reported their functional coupling with TRPV1 channels across multiple disease contexts. In 2006, Sang R. Kim’s team first demonstrated that microglia express TRPV1 channels, whose activation triggers Ca²⁺ signaling, leading to mitochondrial damage and cytochrome C release. This process activates the caspase-3 apoptotic pathway, inducing programmed cell death in microglia, and provides the first evidence that TRPV1 mediates microglial death both in vitro and in vivo (68). Subsequent studies across various disease contexts have progressively revealed the crucial role of TRPV1 channels activation in triggering Ca²⁺ signaling, which is pivotal for neuroimmune regulation centered on microglia. (Figure 3).

Figure 3

Figure 3. The related mechanism of microglia mediated by TRPV1 channel activation in neuroinflammation. (1) The activation of TRPV1 channel triggers Ca²⁺ influx, causing mitochondrial damage, cytochrome C and apoptosis factor release, leading to apoptosis. (2) Aβ can activate TRPV1 channel and induce ROS production in microglia. (3) TRPV1 activation can promote the activation of microglia, macrophages, neutrophils and other immune cells; (4) N-acyi amides can activate TRPV1 channel and aggravate neuroinflammation; (5) Adiponectin has anti-inflammatory and protective effects, and its inhibition can lead to the activation of TRPV1, which mediates MAPK activation and aggravates the inflammatory response. (6) BLA nociceptive signal induced activation of TRPV1 on Glu neurons and activation of pyramidal neurons in PFC cortex. By releasing Glu, glial cells released apoptotic factors, which aggravated neuroinflammation and apoptosis. (7) Activated microglia release Glu vesicles for microglia-neuron communication, aggravating the occurrence of inflammatory response. Created with Figdraw 2.0. (ID: UUTOP6279b).

In the field of neurodegenerative diseases, the accumulation of β-amyloid (Aβ) plaques in the brain and microglia-induced neuroinflammation are considered key components of AD (71). The influx of Ca²⁺ through TRPV1 channel is recognized as a crucial ion channel for Aβ-induced microglial priming and microglial ROS production. Its pathological activation exacerbates oxidative stress and neuroinflammation in AD. Studies have demonstrated that the inhibition of TRPV1 channels can entirely eliminate Aβ-induced acute ROS production, while the inhibition of K⁺ channels does not exhibit a similar effect (72). At the level of cerebrovascular diseases, reports indicate that TRPV1 is upregulated in hemorrhagic brains and is expressed in neurons, microglia, and astrocytes. Inhibition of TRPV1 expression blocks the activation of calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated downstream nociceptive pathways, ultimately reduces the activation of pro-inflammatory microglia/macrophages, decreases the number of infiltrating neutrophils around the hematoma, and attenuates the protein expression of pro-inflammatory cytokines and chemokines, as well as BBB permeability (58).

The role of central sensitization-driven brain TRPV1 channels and microglial activation in regulating systemic immune homeostasis and NP has been extensively demonstrated in numerous studies. The transmission of pain signals originates in the periphery, with the synapse between dorsal root ganglion and spinal dorsal horn neurons serving as the initial site for relaying nociceptive stimuli (73). In the context of inflammatory and NP, the activation of spinal TRPV1 channels significantly promotes glial cell activation, thereby driving the development of central sensitization (74–78). Subsequently, these signals are transmitted to the brain for further processing. Research indicates that peripheral acute inflammation induces peripheral pain and systemic inflammatory responses by driving changes in multiple N-acyl amides at the brain level, specifically within the striatum, HPC, CB, TH, midbrain, and brainstem. This process activates TRPV-mediated calcium mobilization in supraspinal microglia, triggering downstream events such as microglial activation and the release of inflammatory mediators, which ultimately lead to peripheral pain and systemic inflammatory responses (79). Furthermore, adiponectin, an adipose-derived cytokine, is not only present in serum and involved in the regulation of glucose and lipid metabolism, but studies have also shown that it can cross the BBB and enter the cerebrospinal fluid at concentrations 100-fold lower, thereby modulating the activation of immune cells in the brain and exerting anti-inflammatory neuroprotective effects (80, 81). In the partial sciatic nerve ligation (pSNL) model, research has demonstrated that adiponectin limits TRPV1 activation in the dorsal root ganglia, spinal dorsal horn, brain microglia and cortical neurons, suppresses MAPK pathway phosphorylation, and significantly ameliorates mechanical hypersensitivity associated with peripheral and central sensitization (82).

It is noteworthy that nerve injury-induced activation of TRPV1 channels exacerbates neuroinflammatory processes by modulating the interaction networks between microglia and neurons across different brain regions. The prelimbic (PL) cortex and infralimbic (IL) cortex are two crucial subregions of the medial PFC (mPFC) that play vital roles in pain processing. A study has reported that this phenomenon is associated with TRPV1 channel-triggered crosstalk between cortical neurons and glial cells: sciatic nerve injury (SNI) enhances excitatory signaling in PL-IL cortical pyramidal neurons via the basolateral amygdala (BLA)-mPFC circuit while simultaneously promoting the upregulation of TRPV1 channels in glutamatergic neurons. These combined effects lead to glutamate (Glu) overflow events in the PL-IL cortex, subsequently mediating Caspase-3 activation in microglia and the release of Caspase-1 and IL-1β factors in astrocytes, ultimately resulting in neuroinflammatory responses and pain hypersensitivity in peripheral nerve injury models (83). Meanwhile, studies have confirmed the presence of microglia-neuron communication in the ACC of the chronic constriction injury (CCI) model of the sciatic nerve, where TRPV1-activated microglia promote glutamatergic neurotransmission through the release of extracellular vesicles (EVs) (84).

In summary, the TRPV1 channel serves as a pivotal molecular mediator in the immunomodulation of the nervous system. During innate immune responses triggered by CNS injury, the activation of the TRPV1 channel initiates critical calcium signaling. This process not only directly drives the pro-inflammatory phenotypic transformation and apoptosis of microglia but also establishes a bridge for neuron-glia immune communication. In pain-related central sensitization processes, the TRPV1 channel coordinates glial cell activation and inflammatory cytokine release at both spinal and cerebral levels, thereby orchestrating the disruption of neuroimmune homeostasis and the malignant progression of neuroinflammation.

3.3 The inflammatory pathway mediated by brain TRPV1 channel in neuroinflammation

In neuroinflammation, the inflammatory mediators released due to immune cell activation collectively drive the neuroinflammatory cascade by triggering signal transduction within inflammatory signaling networks. Dysregulation of the TRPV1 channel-mediated Ca²⁺ influx disrupts intracellular calcium homeostasis, leading to the abnormal activation of multiple nociceptive pathways. This process involves the phosphorylation of protein kinases, such as PKA/PKC and PI3K, as well as the activation of signaling pathways, including mitogen-activated protein kinases (MAPK) and Nuclear Factor kappa B (NF-κB). These events ultimately result in cellular inflammation and cell death in the brain, causing disruption of the BBB and subsequent neuro-logical dysfunction (Figure 4).

Figure 4

Figure 4. Brain TRPV1 channel activation mediated neuroinflammatory pathway. (1) TRPV1 channel-related PKA/PKC pathway phosphorylation promotes the release of inflammatory factors such as IL-1β and TNF-α, and aggravates inflammatory response and peripheral sensitization. (2) TRPV1 channel activation induces MAPK pathway phosphorylation, which is involved in microglia activation, ROS production, tau protein phosphorylation, BBB protein loss, and promotes the release of inflammatory factors such as IL-6, IL-1β and TNF-α, resulting in apoptosis and BBB destruction. (3) TRPV1 channel activation promotes the expression of PI3K/AKT pathway and MAPK pathway, activates NF-κB pathway, releases pro-inflammatory mediators such as COX-2, down-regulates the levels of protective factors such as IL-10 and TGF-β3, and aggravates the neuroinflammatory response. Created with Figdraw 2.0. (ID:RIOPY5afb1).

The amino acid sequence of TRPV1 contains multiple phosphorylation sites for protein kinase A (PKA) and PKC. The phosphorylation of TRPV1 by PKA and PKC is closely associated with inflammatory signal transduction and the development of hyperalgesia. Furthermore, PKA and PKC can phosphorylate and sensitize the TRPV1 channel, resulting in increased Ca²⁺ influx and establishing a positive feedback loop (85–89). Studies have demonstrated that the removal of the PKC phosphorylation site (TRPV1 S801) in the TRPV1 channel of mice alleviates nociception and inflammatory pain hypersensitivity mediated by PKC phosphorylation in vivo (90). In the dorsal root ganglia (DRG) and spinal dorsal horn of mice with NP, elevated levels of TRPV1 have been reported to mediate the increased activity of PKC and PKA, leading to the activation of downstream inflammatory signaling pathways (91–94). Furthermore, in the context of MS, research has shown that the TRPV1/PKC pathway mediates synaptic abnormalities and neuronal loss induced by IL-1β and TNF-α in the brain (95).

MAPKs are a class of serine/threonine protein kinases that mediate inflammatory responses and apoptosis through three core MAPK subgroups: p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) (96). Studies have demonstrated that the activation of the TRPV1 channel mediates extracellular Ca²⁺ influx in dorsal root ganglion (DRG) neurons, the spinal cord, and the brain. This process activates the MAPK phosphorylation process, triggering microglial activation, ROS production, and inducing apoptosis-mediated cascade reactions (82, 93, 97–100). In the intracerebral hemorrhage (ICH) model, decreased TRPV1 expression significantly downregulates intracellular Ca²⁺ influx and CaMKII phosphorylation, thereby blocking the P38 and JNK MAPK signaling pathways. This leads to reduced levels of factors such as IL-1β, IL-6, and caspase-3, while increasing the expression of BBB-related proteins including ZO-1, occludin, and claudin-5. Consequently, it suppresses pathological processes, including inflammatory responses, neuronal apoptosis, and BBB disruption (58, 101). The hyperphosphorylation and aggregation of brain tau protein are hallmark features of TBI, serving as risk factors for secondary brain damage, including cognitive and behavioral impairments, as well as diseases such as Alzheimer’s (102–104). Relevant studies have found that inhibiting TBI-induced TRPV1 activation can reduce tau protein hyperphosphorylation, attenuate the activation of JNK, P38, and caspase-3, and alleviate apoptosis, thereby exerting neuroprotective effects (105, 106).

The phosphatidylinositol-3 kinase (PI3K)/threonine-protein kinase AKT (protein kinase B, PKB) signaling pathway serves as a pivotal hub for cell survival signals (107). Its excessive activation can directly promote the nuclear translocation and activity of NF-κB, with both mechanisms synergistically enhancing the expression of pro-inflammatory factors and exacerbating neuroinflammatory responses. In addition to the observed activation of TRPV1 channel-regulated NF-κB and PI3K pathways in dorsal root ganglion (DRG) neurons and the spinal cord (108, 109), studies utilizing a cold stress-induced brain injury model have demonstrated that TRPV1 activation in the brain upregulates PI3K/AKT expression, promoting the production of nociceptive mediators such as IL-6, TNF-α, and NF-κB while downregulating the levels of anti-inflammatory factor IL-10 and cell growth differentiation factor TGF-β3, ultimately leading to cerebral inflammatory responses and behavioral deficits (110). The PD model further confirmed that TRPV1 inhibitors ameliorate motor dysfunction by downregulating the activity of the MAPK/NF-κB pathway in the brain striatum and reducing the expression of pro-inflammatory markers such as COX-2 (111). Notably, TRPV1 channel activation exhibits a similar mechanism in the regulation of addictive behaviors. In dorsal root ganglion (DRG) neurons, the spinal cord, and the nucleus accumbens (NAc), TRPV1 promotes the release of inflammatory factors by activating the MAPK/NF-κB pathway, mediating morphine-induced analgesic tolerance and withdrawal responses. Targeted inhibition of TRPV1 receptors can effectively block drug reward effects (112–115).

3.4 DAMP signaling pathway mediated by brain TRPV1 channel in neuroinflammation

In the initiation and progression of neuroinflammation, the release of DAMPs represents a pivotal initial event that triggers and amplifies immune responses. DAMPs are a class of endogenous molecules released by stressed, injured, or necrotic cells into the extracellular space. These molecules function as “danger signals” recognized by pattern recognition receptors, such as TLR4 and RAGE, thereby activating the innate immune system (116). High Mobility Group Box 1 (HMGB1) and S100 calcium-binding protein B (S100B) are key DAMPs in the CNS. Under physiological conditions, they are predominantly localized within neurons and glial cells, but they are extensively released into the extracellular space during pathological states. Not only can they directly activate microglia, but they can also trigger potent pro-inflammatory signaling pathways through receptors such as TLR4 and RAGE, inducing the assembly of the NLRP3 inflammasome and creating a self-amplifying “inflammatory storm” (116, 117). The activation of brain TRPV1 channels is closely linked to the triggering of the DAMPs signaling cascade. TRPV1-mediated Ca²⁺ influx not only directly promotes the release of DAMPs from neurons and glial cells but also forms complex positive feedback loops with downstream DAMPs signaling pathways, collectively constituting a vicious cycle in neuroinflammation (Figure 5).

Figure 5

Figure 5. The activation of the brain TRPV1 channel mediates the DAMP signaling pathway. (1) Stress, as well as injured or necrotic cells and activated glial cells, release DAMPs such as HMGB1 and S100B. (2) The activation of the TRPV1 channel leads to Ca²⁺ influx, which promotes the release of DAMPs and up-regulates the expression of pro-inflammatory mediators. (3) Following activation, the TRPV1 channel interacts with the TLR4 receptor, inhibiting TGF-β1 signal transduction by suppressing TGF-β receptor (TβRI and TβRII) activity, thereby promoting the polarization of microglia towards the pro-inflammatory M1 phenotype while inhibiting M2 phenotype polarization. (4) The TRPV1-Ca²⁺-PP2A pathway facilitates the activation of the NLRP3 inflammasome, exacerbating the inflammatory response and increasing levels of caspase-1, IL-1β, and TNF-α. (5) Additionally, HMGB1, by binding to TLR4 and RAGE receptors, participates in the activation of the NLRP3 inflammasome, further aggravating the inflammatory response. Created with Figdraw 2.0. (ID:UYWUA7c977).

Current studies have indicated that the activation of TRPV1 channels, which mediates Ca²⁺ influx in dorsal root ganglion (DRG) neurons, plays a crucial role in peripheral hyperalgesia by triggering the HMGB1/S100B pathway (118, 119). Similarly, in a cold stress-induced brain injury model, the activation of TRPV1 channels promotes Ca²⁺ influx in the brain, leading to the expression and release of S100B in brain tissue. This process upregulates pro-inflammatory mediators (IL-6, TNF-α, NF-κB) and downregulates anti-inflammatory factors (IL-10, TGF-β), thereby exacerbating neuroinflammation and behavioral deficits. Notably, TRPV1 inhibitors have been shown to reverse these changes (110). In the febrile seizure model, TRPV1 activation results in elevated levels of proinflammatory cytokines, including HMGB1, IL-1β, IL-6, and TNF-α, in the HPC and cortex (120). Extracellular HMGB1 acts as a critical “alarm molecule”, predominantly activating proinflammatory responses through its receptor TLR4 (121). Further studies have revealed that the intracellular Ca²⁺ signaling activated by TRPV1 channels interacts with TLR4 to form a functional complex, collectively promoting the polarization of microglia toward the pro-inflammatory M1 phenotype while suppressing the neuroprotective M2 phenotype and TGF-β receptors (TβRI, TGF-βRII). This mechanism downregulates the expression of genes and proteins involved in transforming growth factor-β1 (TGF-β1) signal transduction and is considered a critical foundation for neuroinflammation-induced epileptogenesis (122).

The TRPV1-Ca²⁺ signaling axis serves as a critical upstream event for the activation of the NLRP3 inflammasome. The inflammasome is a cytosolic multiprotein complex that directly induces cellular damage and death by mediating the initiation and amplification of inflammatory cascades, with the NLRP3 inflammasome being the most extensively studied inflammatory complex to date (123). Current research has highlighted the pivotal role of TRPV1-NLRP3 pathway activation in the dorsal root ganglion (DRG) during peripheral inflammatory pain (124, 125). Furthermore, in the subarachnoid hemorrhage (SAH) model, it has been observed that TRPV1 channel-mediated Ca²⁺ overload in the brain activates the NLRP3 inflammasome in microglia, subsequently upregulating the expression of caspase-1, IL-1β, and TNF-α, thereby exacerbating neuroinflammatory responses in SAH (101). Further related reports indicate the potential role of the TRPV1-Ca²⁺-PP2A pathway in the activation of the NLRP3 inflammasome. Studies demonstrate that protein phosphatase PP2A is not only sensitive to changes in cytoplasmic ion concentrations (such as K+ and Ca²⁺) but also plays a significant role in the dephosphorylation process of NLRP3. The knockout of PP2A has been shown to reduce NLRP3 inflammasome activation (126, 127). In the context of MS, research confirms that microglial TRPV1 mediates Ca²⁺ influx and PP2A activity, thereby regulating NLRP3 inflammasome activation and exacerbating systemic inflammatory responses (128). Additionally, HMGB1 has been demonstrated to participate in NLRP3 inflammasome activation via TLR4 and RAGE signaling, creating a positive feedback loop that amplifies the inflammatory cascade (129).

3.5 Oxidative stress mediated by brain TRPV1 channels in neuroinflammation

Oxidative stress is a critical factor in neuroinflammation. Mitochondrial dysfunction and the inflammatory cascade events caused by neuroinflammation lead to a significant release of ROS in brain tissue. These processes also disrupt the redox system by suppressing the antioxidant system and activating oxidative stress pathways, collectively inducing oxidative stress. In turn, oxidative stress exacerbates cellular damage and inflammatory responses, forming a vicious cycle (130). Peripheral neuropathy and spinal cord injury-induced activation of TRPV1 channels in the dorsal root ganglia (DRG) and spinal cord results in intracellular Ca²⁺ overload. The critical role of activated oxidative stress events in central neuroinflammation and pain has been substantiated in previous studies (131–134). Relevant studies indicate that elevated levels of the oxidative stress marker lipid peroxidation (LPO) in brain tissue are closely associated with calcium overload resulting from TRPV1 activation (135). High intracellular Ca²⁺ concentrations lead to mitochondrial damage, microglial activation, and imbalance in the redox system (Figure 6).

Figure 6

Figure 6. Brain TRPV1 channel activation mediates oxidative stress. (1) TRPV1 channel activation caused mitochondrial damage and cytochrome C, ROS release; (2) TRPV1 channel activation induces microglial activation and ROS production; (3) TRPV1 channel activates Gsk3β oxidative stress pathway, down-regulates the levels of Nrf2, HO-1 and NQO1 antioxidant factors, and aggravates tau protein phosphorylation; (4) TRPV1 channel activation down-regulated the expression of GSH-Px antioxidant pathway and activated the apoptosis pathway. Created with Figdraw 2.0. (ID:ITSTY45a5a).

The mitochondrial dysfunction and inflammatory response caused by TRPV1 channel activation, leading to excessive ROS release, constitute one of the primary causes of oxidative stress events. In vitro studies have demonstrated that the activation of TRPV1 leads to excessive mitochondrial Ca²⁺ loading within cells, which triggers mitochondrial damage and cytochrome C release, mediating the occurrence of cell death (68). Conversely, pharmacological inactivation of TRPV1 reduces Ca²⁺ influx and CaMKII phosphorylation, mitigates neuronal vulnerability to hemin-induced injury, inhibits apoptosis, and preserves mitochondrial integrity in vitro (58). This has been confirmed in cerebral hemorrhage and AD animal model, where activation of TRPV1 channels in the brain triggers increased Ca²⁺ concentration within mitochondria and mitochondrial depolarization, activates microglia, promotes massive ROS production, exacerbates oxidative stress events, aggravates apoptosis and brain damage, ultimately leading to disease progression (72, 100).

The activation of TRPV1 disrupts calcium homeostasis and, by impairing the balance of the redox system, further triggering oxidative stress events. In AD, the deposition of Aβ can promote the production of ROS and disrupt calcium homeostasis, exacerbating tau protein phosphorylation, inducing cell death, and contributing to neurodegeneration (136–139). Studies indicate that this may be associated with TRPV1-mediated Ca²⁺ influx, which activates the glycogen synthase kinase-3β (Gsk3β) oxidative stress pathway, leading to the ubiquitination and degradation of the antioxidant transcription factor E2 (Nrf2). Further studies revealed that inhibiting TRPV1-dependent calcium accumulation and the TRPV1/CaMK pathway downregulated Gsk3β activity. This, in turn, promoted the intracellular accumulation of Nrf2 and upregulated the levels of antioxidant enzymes such as HO-1 and NQO1. This mechanism reversed oxidative stress damage and amyloid-β neuropathology in AD, thereby exerting protective effects (140). Additionally, TRPV1 activation disrupts redox balance by inhibiting the antioxidant system. In cases of diabetes-induced NP, the activation of antioxidant pathways, including glutathione peroxidase (GSH-Px), has been shown to downregulate TRPV1 expression in the dorsal root ganglia and HPC. This mechanism mitigates tissue oxidative stress and apoptosis by blocking Ca²⁺ influx-induced mitochondrial damage and reducing the release of apoptotic factors such as caspase 3 and 9 (141).

3.6 Synaptic plasticity regulation mediated by brain TRPV1 channels in neuroinflammation

Persistent neuroinflammation, oxidative stress, and related events lead to neuronal damage and death, resulting in dysregulation of synaptic plasticity in the brain and impairment of nervous system function. These processes are implicated in the pathogenesis of EP, PD, and Huntington’s disease, and are closely associated with functional impairments in the brain, such as mood disorders, cognitive deficits, and drug addiction (142, 143). Studies have demonstrated that TRPV1 channel-mediated calcium regulation not only modulates synaptic plasticity and nociceptive transmission at the spinal level (77, 144–146), but also participates in the pathological mechanisms of neural dysfunction across various brain regions involved in movement, cognition, and emotion. In the progression of disease, neuroexcitatory regulation mediated by brain TRPV1 channels disrupts the balance between inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA), and excitatory neurotransmitters, including Glu, leading to alterations in synaptic strength characterized by long-term potentiation (LTP) and long-term depression (LTD) (Figure 7). This process concurrently activates glial cells, and the inflammatory factors they release further exacerbate excitotoxicity and synaptic dysfunction. Ultimately, abnormal neuronal activity, impaired synaptic plasticity, and neuroimmune responses create a vicious cycle that collectively drives the progressive impairment of brain function. Relevant studies have evaluated the effects of TRPV1 channel activation-mediated neuroinflammation on brain functions, such as mood, cognition, and drug addiction, under different contexts, confirming the association between cerebral TRPV1 channel activation and corresponding brain functional alterations across various disease conditions.

The TRPV1 channel drives synaptic excitotoxicity through the “calcium signaling-glutamate release-NMDAR activation” axis. TRPV1 is expressed in both glutamatergic and GABAergic neurons (147, 148). Glu is the predominant excitatory neurotransmitter in the CNS. Research indicates that TRPV1-mediated Ca²⁺ influx synergizes with calcium release from intracellular stores, significantly elevating local calcium concentrations and promoting microglial vesicle shedding. This process indirectly facilitates the abnormal activation of Glu receptors, primarily N-methyl-D-aspartate receptors (NMDAR), alters excitatory postsynaptic currents (EPSCs), and ultimately leads to excitotoxic neuronal damage (84, 149–151). Furthermore, it has been reported that cytokines such as IL-1β and TNF-α, secreted by immune cells, can regulate glutamate-mediated central synaptic transmission. The brain’s TRPV1 channels are implicated in glutamate-mediated central synaptic transmission and neurotoxic effects, exacerbating MS-induced synaptic dysfunction and neuronal loss (95). Additionally, research indicates that TRPV1 channels facilitate neuronal Glu release and increase EPSC frequency in brain regions such as the SSC and striatum, providing significant insights into the mechanisms underlying motor control disorders, including Parkinson’s and Huntington’s diseases (152, 153). Meanwhile, research on NP models has confirmed that pain signals can activate TRPV1 in glutamatergic neurons, resulting in extracellular Glu spillover, activation of glial cells, and ultimately leading to neuroinflammatory responses and pain hypersensitivity in models of peripheral nerve injury (83, 154).

The TRPV1-glutamate signaling directly regulates LTP/LTD, serving as the synaptic basis for learning, memory, and emotional behaviors. LTP and LTD are crucial forms of synaptic plasticity, characterized by sustained increases or persistent suppression of synaptic transmission efficiency, respectively. An imbalance between LTP and LTD leads to altered synaptic plasticity, which serves as a key mechanism underlying the hyperexcitable state observed during epileptic activity. Research indicates that TRPV1 is upregulated and activated during epileptic seizures, subsequently triggering Glu release and mediating enhanced LTP while suppressing LTD in neuronal synapses, resulting in an excitation/inhibition imbalance (148, 155–157). In TRPV1 knockout animals, weakened LTP and abolished LTD have been observed (158–160), confirming the critical role of TRPV1-mediated Glu release and alterations in synaptic strength in the process of epileptogenesis.

The functional antagonism between TRPV1 and CB1R finely regulates synaptic plasticity related to emotion and cognition. It is noteworthy that synaptic plasticity mediated by the TRPV1 channel is closely associated with anxiety and depression-like mood disorders, as well as cognitive deficits, including learning and memory impairments caused by neuroinflammatory damage. The CB1 receptor (CB1R), a core component of the endocannabinoid system, is intimately linked to GABA transmission and forms a functionally antagonistic regulatory axis with TRPV1 in the CNS (148, 161). Studies demonstrate that these two receptors exhibit significant spatial co-expression patterns in key brain regions involved in emotional regulation, such as mPFC, PAG, NAc shell, and HPC (162–167), although their neurobiological effects display functional polarization. The signaling transduction pathway activated by CB1R exerts anxiolytic and antidepressant effects by inhibiting neural activity and neurotransmitter release (168–171), whereas TRPV1 channel enhances synaptic excitability by promoting Glu release, activating NMDAR Glu receptors, and facilitating LTP. This activity increases anxiety, depression, fear-like behaviors, and impairs cognitive functions such as learning and memory (147, 160, 168–170, 172–176). The functional differentiation of these receptors based on brain region specificity provides novel molecular targets for developing precise therapeutic strategies for neuropsychiatric disorders.

4 Acupuncture ameliorates neuroinflammation by modulating TRPV1 channels in the brain

As a non-pharmacological intervention, acupuncture has garnered widespread attention from researchers worldwide due to its demonstrated anti-inflammatory and analgesic effects, as well as its fewer side effects and lower risk of tolerance. According to data from the NIH, over 15 million Americans have received acupuncture treatment, indicating a significant upward trend (177, 178). Currently, acupuncture therapy is extensively applied in the fields of inflammatory diseases, pain management, and mood disorders (179), with its neuroimmune regulatory effects being well-documented (180–182). Growing evidence suggests that brain TRPV1 channels serve as promising therapeutic targets for neuroimmune modulation in the CNS diseases and inflammation-related central sensitization. Recent studies have highlighted the close relationship between cutaneous stimulation signals from acupuncture and alterations in TRPV1 channels. Our research has focused on examining changes in the expression and function of TRPV1 channels at the cerebral level, as well as their mechanisms in acupuncture intervention. This work emphasizes the pivotal regulatory role of TRPV1 channels as cation channel proteins across multiple domains, including neuroprotection, pain modulation, emotional and behavioral regulation, and cognitive function. These effects involve the modulation of immune cell activation, inflammatory pathway signaling, DAMPs signaling activation, oxidative stress responses, and neurotoxicity pathways (Figure 7, Table 1).

Figure 7

Figure 7. Brain TRPV1 channel activation mediates synaptic plasticity disorders. (1) TRPV1 activation promotes the release of Glu, resulting in the activation of NMDAR-based Glu receptors, resulting in neurotoxicity. (2) TRPV1 activation causes LTP/LTD imbalance, resulting in LTP enhancement and LTD inhibition. Created with Figdraw 2.0. (ID:TARRT0abd3). (3) Forming a pathway of TRPV1 activation-glutamate release-NMDAR activation-synaptic plasticity alteration.

Table 1

Table 1. Summary of research on brain TRPV1 channel mediated acupuncture effect.

4.1 Acupuncture therapy and its protective effects in neuroinflammation

Acupuncture is a surface stimulation method that regulates bodily functions by targeting specific areas of the body known as acupoints. Since the 1970s, acupuncture has gradually gained global popularity (204). In 1990, standardized nomenclature and localization criteria for acupuncture points were established, which have since undergone continuous revision and refinement, significantly enhancing their scientific validity and authority in recent decades (205). Currently, the primary stimulation methods in acupuncture include manual needling and EA. With advancements in modern medicine, innovative techniques such as acupoint catgut embedding have been further developed. This technique involves implanting absorbable medical catgut sutures or collagen threads into specific acupoints using specialized needles, allowing for continuous stimulation of the targeted acupoints for several weeks until the sutures are completely absorbed. This method achieves prolonged anti-inflammatory and analgesic effects (31, 206). In recent decades, extensive research has demonstrated that acupuncture exerts significant neuroprotective effects in alleviating symptoms of CFS, chronic pain, ischemic stroke, PD, AD, and other neurological disorders. Furthermore, it has been shown to improve cognitive impairment, anxiety, depression, and other mental-emotional conditions by reducing inflammatory responses (207–216). Additionally, a series of studies have confirmed that the neuroinflammatory protective effects of acupuncture are associated with its modulation of multiple pathways in the brain, including immune cell activity, inflammatory signaling pathways, DAMPs signaling activation, oxidative stress, and synaptic plasticity (28, 29, 217–220).

4.2 Acupuncture modulates brain TRPV1 channel-mediated immune cell activity to ameliorate neuroinflammation

Acupuncture treatment has been shown to inhibit the upregulation of TRPV1 and glial cells in the spinal cord of mice experiencing inflammatory pain, thereby exerting anti-inflammatory and analgesic effects while reducing pain-related behaviors in these animals (221, 222). Furthermore, acupuncture is demonstrated to suppress the expression of TRPV1 channels in the brain, decrease calcium ion influx, directly regulate the activation of central glial cells—primarily microglia and astrocytes—modulate peripheral-central immune crosstalk, inhibit the release of nociceptive mediators, and exert neuroprotective effects (Figure 8a). Causal evidence from TRPV1 channel gene knockout and pharmacological studies strongly supports this mechanism: in the Middle cerebral artery occlusion model (MCAO), EA preconditioning significantly suppressed TRPV1 expression and glial cell proliferation in the hippocampal region, reduced neuronal apoptosis, and cerebral infarct volume. Notably, the application of the TRPV1 agonist capsaicin abolished these protective effects, confirming that acupuncture’s modulation of immune cell activity is closely associated with its inhibition of TRPV1 channel activation (183). Further studies have confirmed that acupuncture interventions in FM models downregulate the activity of TRPV1 channel receptors across several key brain regions, including the spinal cord, dorsal root ganglia, prefrontal cortex (PFC), somatosensory cortex (SSC), anterior cingulate cortex (ACC), TH, AMY, hypothalamus, PAG, and cerebellar lobules V, VI, and VII. This intervention reduces the expression of glial cell markers such as GFAP and Iba-1, inhibits downstream inflammatory cascades, alleviates neuroinflammatory responses in the brain, and improves mechanical and thermal hyperalgesia in animal models. These findings have been validated in Trpv1 gene knockout mice (184–188, 201). Furthermore, recent studies have shown that FM-induced TRPV1 activation triggers increased expression of IL-17 receptors and IL-17 factors associated with CD4+ helper T cells (Th) in the brain, further stimulating the transmission of inflammatory signaling pathways and exacerbating neuroinflammation. This pathway is blocked in Trpv1-/- mice and under EA treatment by attenuating the expression of the TRPV1-IL-17 related pathway, effectively alleviating central neuroinflammation and mechanical/thermal hyperalgesia behaviors in mice. This provides direct causal evidence for the “central TRPV1-adaptive immunity” dialogue (189).

Meanwhile, the inhibition of central TRPV1 by acupuncture can also produce systemic anti-inflammatory effects. A series of studies have analyzed relevant cellular markers and inflammatory mediators in peripheral plasma. The results indicate that acupuncture exerts anti-inflammatory effects by downregulating cerebral TRPV1 expression in neuroinflammation, thereby inhibiting the release of pro-inflammatory factors associated with peripheral immune cells, including monocytes, macrophages, and T cells. These pro-inflammatory factors include monocyte chemoattractant protein-1 (MCP-1), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-2, IL-5, IL-6, IL-12, and IL-17, while simultaneously upregulating the anti-inflammatory factor IL-10 (121, 186, 188–192). This indicates that acupuncture coordinates systemic immune homeostasis through this central target.

4.3 Acupuncture modulates brain TRPV1 channel-mediated inflammatory signaling pathway to ameliorate neuroinflammation

The study demonstrates that acupuncture exerts anti-inflammatory and anti-apoptotic protective effects in neuroinflammation by modulating TRPV1 channel activation, thereby reversing abnormal intracellular inflammatory signaling pathways (Figure 8b). A series of studies have demonstrated that acupuncture inhibits the activation of TRPV1 channels in the dorsal root ganglion (DRG) and spinal cord (SC), maintains calcium homeostasis, and suppresses downstream kinase pathway activation to regulate pain signaling (200, 223–226). At the cerebral level, acupuncture specifically inhibits the overactivation of TRPV1 channels in neurons and microglia within key brain regions of the FM model, including the medial prefrontal cortex (mPFC), SSC, ACC, hypothalamus, HPC, TH, PAG, and CB. This action reduces Ca²⁺ influx-dependent activation of PKA, PKC, and PI3K kinases, subsequently blocking downstream MAPK and NF-κB signaling cascades. Consequently, it decreases the release of inflammatory mediators and neural damage, thereby ameliorating mechanical and thermal hyperalgesia (184–191, 193–195, 197, 200, 202, 203), as well as depressive-like behaviors (192, 196) in animal models. In the cerebral ischemia (CI) model, acupuncture exerts protective effects by downregulating TRPV1 expression in hippocampal neurons, inhibiting NF-κB signaling pathway activation, modulating the imbalance in the Bax/Bcl-2 apoptotic protein ratio, and caspase-3 release, ultimately reducing neuronal apoptosis and cerebral infarct area. Additionally, studies have shown that acupuncture suppresses TRPV1 expression in the HPC and PFC of PD mice, along with downstream inflammatory pathways such as PKA/PKC/PI3K/MAPK, alleviating neuroinflammation and improving spatial learning dysfunction and cognitive abilities in PDD mice (121).

4.4 Acupuncture regulates brain TRPV1 channel-mediated DAMPs signaling pathway to improve neuroinflammation

Acupuncture can effectively intervene in the overactivation of neuroimmune signaling mediated by DAMPs by inhibiting central TRPV1 channels, thereby blocking the amplification of inflammatory signals. Existing studies have reported that EA exerts anti-inflammatory and analgesic effects by suppressing the overexpression of TRPV1 in the dorsal root ganglia (DRG) and spinal cord, as well as DAMPs signaling (Figure 8c) (222, 224). Moreover, in FM models, acupuncture reduces the activity of TRPV1 channels in multiple central regions, including the spinal cord, dorsal root ganglia, PFC, SSC, ACC, TH, AMY, hypothalamus, PAG, and CB. This reduction decreases Ca²⁺ influx-driven immune cell activation and downstream DAMPs pathway activation, leading to lowered levels of HMGB1 and S100B (184–186). Consequently, acupuncture blocks the binding of these molecules to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE), inhibiting key inflammatory signal amplification pathways (187, 188, 201). This mechanism ultimately ameliorates chronic mechanical and thermal hyperalgesia behaviors in pain models.

4.5 Acupuncture modulates oxidative stress mediated by brain TRPV1 channels to ameliorate neuroinflammation

The anti-inflammatory and analgesic effects of EA have been documented through the downregulation of inflammation-related molecules and oxidative stress markers, such as superoxide dismutase (SOD) and catalase (CAT), in the spinal cord (225). Limited evidence indicates that acupuncture offers protective effects against oxidative stress in neuroinflammation by alleviating mitochondrial damage and regulating the balance of the redox system through modulation of TRPV1 channels, which in turn reduces ROS levels (Figure 8d). Studies have demonstrated that EA stimulation mitigates mitochondrial damage in neural cells induced by CI through the regulation of brain TRPV1 expression and Ca²⁺ influx (183). This intervention decreases the release of cytochrome C and malondialdehyde (MDA), enhances antioxidant factors such as glutathione (GSH), SOD, and CAT, reduces levels of TNF-α and IL-1β, and ameliorates oxidative stress and inflammatory responses associated with cerebral ischemia-reperfusion injury, lowers neurological deficit scores in middle cerebral artery occlusion (MCAO) rats, and diminishes cerebral infarct volume (198, 227).

4.6 Acupuncture modulates synaptic plasticity mediated by brain TRPV1 channels to ameliorate neuroinflammation

Relevant studies suggest that acupuncture may enhance synaptic plasticity and reduce neuroinflammation by suppressing the expression of TRPV1 channels. This includes modulation of neurotransmitter transmission and receptor expression, which together ameliorate abnormal synaptic transmission (Figure 8e). A 2010 study first demonstrated that EA stimulation at Baihui (GV20) could downregulate TRPV1 overexpression induced by ischemic brain injury in the hippocampal CA1 region, alleviate glutamate-mediated neurotoxicity, and inhibit NMDAR activation, consequently improving LTP impairment and behavioral deficits (199). Subsequent studies further revealed that in a mouse model of chronic pain and depression comorbidity, acupuncture treatment targeting cerebellar regions V, VI, and VII not only downregulated NMDAR expression via the TRPV1 pathway but also enhanced the release of the inhibitory neurotransmitter GABA, alleviating mechanical and thermal hyperalgesia as well as depressive-like behaviors (196). Notably, the latest research found that acupuncture in FM mouse models, by inhibiting TRPV1 channel activation, as well as the activation of glial cells, increased CB1R expression in the dorsal root ganglia (DRG), spinal cord PAG, and hypothalamus. Consequently, this leads to a reduction in Ca²⁺ influx, suppression of neuronal excitability, and inhibition of synaptic transmission within nociceptive pathways (197, 201). These findings demonstrate that the anti-inflammatory and analgesic effects of acupuncture stimulation are closely associated with the restoration of excitatory-inhibitory balance in the CNS. However, most studies on the role of TRPV1 channels in emotional and cognitive disorders are based on animal models, with limited clinical translational evidence available to date. Dummy Figure 8.

Figure 8

Figure 8. Acupuncture exerts protective effects against neuroinflammation by suppressing TRPV1 activity. (a)Acupuncture inhibits immune cell activation by inhibiting TRPV1 channel-mediated Ca²⁺ influx; (b) Acupuncture inhibits Ca²⁺ influx and the transmission of inflammatory signaling pathways by downregulating TRPV1 expression; (c) Acupuncture blocks the amplification of inflammatory signals by inhibiting TRPV1 channel-mediated Ca²⁺ influx, thereby attenuating DAMPs signaling and the subsequent activation of TLR3 and RAGE receptors; (d) Acupuncture mitigates oxidative stress and activates antioxidant pathways through TRPV1 suppression; (e) Acupuncture modulates the excitatory-inhibitory balance of the nervous system by regulating the transmission of excitatory and inhibitory neurotransmitters, as well as the expression of related receptors, via TRPV1 inhibition. Created with Figdraw 2.0. (ID:UTOAS41e73).

5 Conclusions and view

Neuroinflammation is a key driver of pathological changes in the nervous system, promoting the progression of neurological disorders and causing irreversible damage to brain structure and function. This issue has garnered widespread attention from researchers worldwide. This review systematically elucidates that TRPV1 channel-mediated Ca²⁺ influx serves as a central node in the immune-inflammatory network during the pathological processes of the nervous system. At both peripheral and spinal levels, TRPV1 channels function as the “gateway” for nociceptive signal transmission and primary central sensitization. Their activation directly triggers immune responses in glial cells and facilitates the cascade release of neurotransmitters by disrupting calcium ion homeostasis, thereby amplifying inflammatory signals, promoting peripheral sensitization, and relaying these signals to the brain. At the cerebral level, TRPV1 channels induce calcium overload by responding to ascending and central intrinsic signals, which disrupts brain immune homeostasis. This subsequently activates inflammatory pathways such as PKA/PKC/MAPK, PI3K, NF-κB, as well as DAMPs pathways, triggering potent inflammatory responses and oxidative stress. These processes disrupt the central excitation/inhibition balance, collectively forming a vicious cycle that persistently exacerbates neuroinflammation and neuronal damage. This progression drives pathological changes in the nervous system and leads to functional impairments in higher brain centers governing sensation, motor control, emotion, and cognition.

Acupuncture therapy, an essential component of traditional Chinese medicine, boasts a long history and a unique theoretical system. It involves stimulating specific acupoints on the human body with specialized needles to regulate physiological functions and treat diseases, demonstrating remarkable anti-inflammatory and analgesic effects in medical practice. With the standardization of acupuncture therapy systems-including the gradual unification of acupoint localization, operational protocols, and stimulation parameters, significant progress has been made in fundamental research on its mechanisms of action (205, 228, 229). Through a comprehensive review of the pathophysiology of neuroinflammation and related disorders, as well as an exploration of the role of TRPV1 channels in neuroinflammatory regulation, we highlight the potential therapeutic efficacy of acupuncture in modulating neuroinflammation via brain TRPV1 channels across various disease contexts (Table 2). Firstly, it is evident that acupuncture exerts anti-inflammatory and analgesic effects by suppressing TRPV1 channel expression in peripheral nerves, dorsal root ganglia (DRG), and the spinal cord, thereby attenuating the transmission of nociceptive signals. Secondly, acupuncture alleviates the central immune-inflammatory cascade by downregulating the overexpression of TRPV1 channels in the brain. The specific mechanisms include: (1) inhibiting the activation of central immune cells and reducing the release of pro-inflammatory factors; (2) blocking Ca²⁺-dependent inflammatory signaling pathways such as PI3K/MAPK/NF-κB, thereby mitigating cell apoptosis and blood-brain barrier disruption; (3) suppressing DAMPs signaling pathways to prevent excessive activation of inflammatory responses; (4) ameliorating mitochondrial dysfunction and redox system imbalance to reduce oxidative stress levels; (5) modulating the balance of Glu and GABA neurotransmitters and the expression of NMDAR and CB1R to improve synaptic plasticity dysfunction. In summary, while acupuncture signals inhibit peripheral and spinal TRPV1 channel activity to attenuate nociceptive input, they also modulate cerebral TRPV1 channels to ‘repair the CNS’. This bidirectional synergistic regulation collectively forms the comprehensive biological basis for its systemic anti-inflammatory and analgesic effects. This not only provides insights for modulating inflammatory responses caused by nervous system injuries but also holds significant implications for the treatment and prevention of brain dysfunctions—including motor, sensory, emotional, and cognitive impairments—resulting from such injuries.

Table 2

Table 2. The mechanism of acupuncture regulating different nervous system diseases.

This study systematically reviews the potential mechanisms through which acupuncture modulates neuroinflammation via the TRPV1 channel in the brain, highlighting its therapeutic potential. However, several important limitations and unresolved questions persist in this field, which will provide critical directions for future research:

1. The ascending regulatory mechanism remains unclear: it is still not fully understood how the physical stimulation of acupuncture on the body surface is converted into biological signals and transmitted to the brain through specific neural or humoral pathways, precisely regulating the expression and function of TRPV1. Studies have demonstrated that EA can downregulate TRPV1 channel expression and reduce the release of inflammatory factors while simultaneously increasing the levels of α7 nicotinic receptors and parvalbumin (121). This suggests its potential activation of the α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated cholinergic anti-inflammatory pathway (CAIP) (230). However, the relationship between brain TRPV1 channels and α7nAChR in the anti-inflammatory effects of acupuncture necessitates further investigation.

2. Acupoint specificity and complex dose-effect relationships: Although acupuncture therapy is widely applied, controversies persist regarding its acupoint specificity and the dose-effect relationships of stimulation parameters. Figure 9 summarizes the currently reported acupoints, stimulation parameters, and corresponding mechanisms in studies investigating TRPV1 channel modulation in the brain via acupuncture. Currently, research in this field predominantly focuses on pain-related studies, while investigations into neurodegeneration remain at a preliminary stage. The selection of acupoints is primarily concentrated on specific points such as ST36, but whether they possess specificity still requires verification through acupoint-sham point controlled trials. Furthermore, the quantitative relationship between acupuncture parameters (combinations, frequency, intensity) and TRPV1 channel gating characteristics (such as desensitization/sensitization thresholds and calcium-dependent inactivation) remains unestablished. Additionally, there is a lack of precise regulatory strategies based on neuroanatomical and functional connectivity. In the future, it will be necessary to establish a standardized mapping system for “stimulation parameters-biological effects” by utilizing electrophysiology and calcium imaging techniques to facilitate precise interventions.

3. Biphasic and context-dependent functions of TRPV1 channels: It is noteworthy that while this review primarily focuses on the pro-inflammatory role of TRPV1 channels in neuroinflammation, studies have demonstrated that TRPV1 expression is reduced in specific brain regions in certain disease models, where it instead exerts protective effects. These protective effects are associated with its role in mediating autophagy regulation (231–241). Research indicates that mild to moderate autophagy can maintain CNS homeostasis, whereas sustained or excessive autophagy may lead to increased accumulation of autophagosomes in the cytoplasm, degradation of essential components, or even trigger autophagic cell death or other forms of cell death mechanisms (242). Acupuncture therapy is believed to alleviate disease symptoms through the bidirectional regulation of autophagy, although its underlying mechanisms remain insufficiently explored (243). This suggests that the role of TRPV1 channels in the nervous system is not singular; rather, their ultimate effects may form a functional continuum dependent on key factors such as disease stage, cell type, and microenvironment. Future research should focus on identifying the molecular switches (e.g., specific phosphorylation sites or interacting proteins) that transition TRPV1 channel function from “pro-inflammatory” to “protective”, thereby providing a foundation for developing highly selective and context-adaptive regulatory strategies.

4. Challenges in clinical translation and precision medicine: Currently, most evidence is derived from animal models, with extremely limited human data available. Future research urgently requires validation through clinical imaging techniques, such as fMRI and PET, or through biomarker detection studies. Ultimately, studies should integrate multiomics technologies, neural circuit tracing, and clinical data to analyze individual differences based on the TRPV1 signaling network. This integration aims to advance acupuncture from ‘empirical medicine’ to a new level of ‘precision medicine’ that is tailored to patients’ genetic backgrounds, disease types, and neuroimmune statuses.

Figure 9

Figure 9. Stimulation parameters and related mechanisms of acupuncture intervention in different disease models. To explore the therapeutic mechanism and parameter rules of acupuncture regulating TRPV1 channel, including acupoint selection, acupuncture intervention method, intensity/frequency of EA, depth/specification of acupoint catgut embedding, to evaluate its immunomodulatory potential in neuroinflammation-related diseases model such as SIN (175), Intermittent cold-stress (ICS) (176, 178, 180, 181, 204, 206, 208, 223, 229), CIP (172), Cold stress pain (CSP) (177), CFM (191), Complete freund’s adjuvant (CFA) (174, 182, 205), AS (207, 228), PDD (179), Cerebral ischemia reperfusion injury (CIRI) (173, 209), MCAO (211), and to provide a basis for the development of targeted acupuncture therapy. By Origin 2024.

Author contributions

QT: Validation, Visualization, Writing – original draft, Writing – review & editing, Conceptualization. MH: Methodology, Supervision, Writing – original draft. PZ: Writing – review & editing. MS: Writing – review & editing. JC: Writing – review & editing. QZ: Software, Writing – review & editing. JH: Data curation, Writing – review & editing. RS: Data curation, Writing – review & editing. BZ: Funding acquisition, Supervision, Writing – review & editing. TL: Supervision, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This research was funded by grants from the National Natural Science Foundation of China (Grant 82230123).

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s)declare that Generative Al was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Glossary

CNS: Central nervous system

PNS: Peripheral nervous system

AD: Alzheimer’s disease

EP: Epilepsy

PD: Parkinson’s disease

TBI: Traumatic brain injury

ICH: intracerebral hemorrhage

CI: cerebral ischemia

MS: Multiple sclerosis

SCI: Spinal cord injury

SAH: Subarachnoid hemorrhage

PND: peripheral nerve disorders

DN: Diabetic neuropathy

FM: Fibromyalgia

NP: Neuropathic pain

CFS: Chronic fatigue syndrome

IP: inflammatory pain

NIH: National Institutes of Health

SPARC: Stimulating Peripheral Activity to Relieve Conditions

TRP: transient receptor potential

TRPV1: Transient receptor potential vanilloid 1

ARD: ankyrin repeat domain

ANS: autonomic nervous system

ACC: Anterior cingulate cortex

SSC: Somatosensory cortex

PFC: Prefrontal cortex

mPFC: medial prefrontal cortex

PAG: Periaqueductal gray

HPC: Hippocampus

TH: Thalamus

AMY: Amygdala

CB: Cerebellum

ROS: Reactive oxygen species

BLA: the basolateral amygdala

Glu: Glutamate

Aβ: β-amyloid

TLR4: Toll-like receptor 4

TGF-β1: Transforming growth factor-β1

TβRI: TGF-β receptor I

TβRII: TGF-β receptor II

pSNL: Partial sciatic nerve ligation

SIN: Sciatic nerve injury

ICS: intermittent cold-stress

CIP: chronic inflammatory pain

CSP: cold stress pain

CFM: chronic fibromyalgia

CFA: complete freund’s adjuvant

AS: Acid-Saline

CCI: Chronic constriction injury

EVs: Extracellular vesicles

MAPK: Mitogen-activated protein kinases

NF-κB: Nuclear Factor kappa B

PKA: Protein kinase A

PKB: protein kinase B

PKC: Protein kinase C

JNK: c-Jun N-terminal kinase

ERK: extracellular signal-regulated kinase

CaMKII: Calmodulin-dependent protein kinase II

PI3K: Phosphatidylinositol 3-kinase

NAc: Nucleus accumbens

LPO: Lipid peroxidation

Gsk3β: glycogen synthase kinase-β

Nrf2: Antioxidant transcription factor E2

GSH-Px: Glutathione peroxidase

GABA: γ-aminobutyric acid

LTP: Long-term potentiation

LTD: long-term depression

NMDAR: N-methyl-D-aspartate receptor

EPSCs: Excitatory postsynaptic currents

CB1R: CB1 receptor

EA: Electroacupuncture

MA: Manual acupuncture

CIRI: cerebral ischemia reperfusion injury

MCAO: Middle cerebral artery occlusion

DMAPs: Damage-associated molecular patterns

MDA: Malondialdehyde

SOD: superoxide dismutase

CAT: catalase

CAIP: cholinergic anti-inflammatory pathway

ST36: Zusanli

LI4: Hegu

GV20: Baihui

BL23: Shenshu

SP6: Sanyinjiao

KI3: Taixi

α7 nicotinic acetylcholine receptor: α7 nAChR

References

1. Brambilla R. Neuroinflammation, the thread connecting neurological disease: Cluster: “Neuroinflammatory mechanisms in neurodegenerative disorders. Acta Neuropathol. (2019) 137:689–91. doi: 10.1007/s00401-019-02009-9

PubMed Abstract | Crossref Full Text | Google Scholar

2. Carson MJ, Thrash JC, and Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res. (2006) 6:237–45. doi: 10.1016/j.cnr.2006.09.004

PubMed Abstract | Crossref Full Text | Google Scholar

3. Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, and Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol. (2019) 10:1008. doi: 10.3389/fphar.2019.01008

PubMed Abstract | Crossref Full Text | Google Scholar

4. Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, et al. Recent research trends in neuroinflammatory and neurodegenerative disorders. Cells. (2024) 13:511. doi: 10.3390/cells13060511

PubMed Abstract | Crossref Full Text | Google Scholar

5. DiSabato DJ, Quan N, and Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. (2016) 139 Suppl 2:136–53. doi: 10.1111/jnc

PubMed Abstract | Crossref Full Text | Google Scholar

6. Latremoliere A and Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. (2009) 10:895–926. doi: 10.1016/j.jpain.2009.06.012

PubMed Abstract | Crossref Full Text | Google Scholar

7. Fang XX, Zhai MN, Zhu M, He C, Wang H, Wang J, et al. Inflammation in pathogenesis of chronic pain: Foe and friend. Mol Pain. (2023) 19:17448069231178176. doi: 10.1177/17448069231178176

PubMed Abstract | Crossref Full Text | Google Scholar

8. Wen B, Pan Y, Cheng J, Xu L, and Xu J. The role of neuroinflammation in complex regional pain syndrome: A comprehensive review. J Pain Res. (2023) 16:3061–73. doi: 10.2147/JPR.S423733

PubMed Abstract | Crossref Full Text | Google Scholar

9. Xiong HY, Hendrix J, Schabrun S, Wyns A, Campenhout JV, Nijs J, et al. The role of the brain-derived neurotrophic factor in chronic pain: links to central sensitization and neuroinflammation. Biomolecules. (2024) 14:71. doi: 10.3390/biom14010071

PubMed Abstract | Crossref Full Text | Google Scholar

10. Adams GR, Gandhi W, Harrison R, van Reekum CM, Wood-Anderson D, Gilron I, et al. Do “central sensitization” questionnaires reflect measures of nociceptive sensitization or psychological constructs? A systematic review and meta-analyses. Pain. (2023) 164:1222–39. doi: 10.1097/j.pain.0000000000002830

PubMed Abstract | Crossref Full Text | Google Scholar

11. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. (2024) 23:344–81. doi: 10.1016/S1474-4422(24)00038-3

PubMed Abstract | Crossref Full Text | Google Scholar

12. Editorial. Sex, gender, and the cost of neurological disorders. Lancet Neurol. (2023) 22:367. doi: 10.1016/S1474-4422(23)00120-5

PubMed Abstract | Crossref Full Text | Google Scholar

13. Ji RR, Nackley A, Huh Y, Terrando N, and Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. (2018) 129:343–66. doi: 10.1097/ALN.0000000000002130

PubMed Abstract | Crossref Full Text | Google Scholar

14. Siracusa R, Paola RD, Cuzzocrea S, and Impellizzeri D. Fibromyalgia: pathogenesis, mechanisms, diagnosis and treatment options update. Int J Mol Sci. (2021) 22:3891. doi: 10.3390/ijms22083891

PubMed Abstract | Crossref Full Text | Google Scholar

15. Meeus M and Nijs J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin Rheumatol. (2007) 26:465–73. doi: 10.1007/s10067-006-0433-9

PubMed Abstract | Crossref Full Text | Google Scholar

16. Scheuren PS and Calvo M. Exploring neuroinflammation: A key driver in neuropathic pain disorders. Int Rev Neurobiol. (2024) 179:311–38. doi: 10.1016/bs.irn.2024.10.009

PubMed Abstract | Crossref Full Text | Google Scholar

17. Shaw BC, Anders VR, Tinkey RA, Habean ML, Brock OD, Frostino BJ, et al. Immunity impacts cognitive deficits across neurological disorders. J Neurochem. (2024) 168:3512–35. doi: 10.1111/jnc.15999

PubMed Abstract | Crossref Full Text | Google Scholar

18. Wang C, Wang J, Zhu Z, Hu J, and Lin Y. Spotlight on pro-inflammatory chemokines: regulators of cellular communication in cognitive impairment. Front Immunol. (2024) 15:1421076. doi: 10.3389/fimmu.2024.1421076

PubMed Abstract | Crossref Full Text | Google Scholar

19. Mingardi J, Meanti R, Paoli C, Cifani C, Torsello A, Popoli M, et al. Ghrelin, neuroinflammation, oxidative stress, and mood disorders: what are the connections? Curr Neuropharmacol. (2025) 23:172–86. doi: 10.2174/1570159X22999240722095039

PubMed Abstract | Crossref Full Text | Google Scholar

20. Amodeo G, Magni G, Galimberti G, Riboldi B, Franchi S, Sacerdote P, et al. Neuroinflammation in osteoarthritis: From pain to mood disorders. Biochem Pharmacol. (2024) 228:116182. doi: 10.1016/j.bcp.2024.116182

PubMed Abstract | Crossref Full Text | Google Scholar

21. Kocamer Şahin Ş and Aslan E. Inflammation as a neurobiological mechanism of cognitive impairment in psychological stress. J Integr Neurosci. (2024) 23:101. doi: 10.31083/j.jin2305101

PubMed Abstract | Crossref Full Text | Google Scholar

22. Mukhtar I. Unravelling the critical role of neuroinflammation in epilepsy-associated neuropsychiatric comorbidities: A review. Prog Neuropsychopharmacol Biol Psychiatry. (2025) 136:111135. doi: 10.1016/j.pnpbp.2024.111135

PubMed Abstract | Crossref Full Text | Google Scholar

23. Granerod J, Huang Y, Davies NWS, Sequeira PC, Mwapasa V, Rupali P, et al. Global landscape of encephalitis: key priorities to reduce future disease burden. Clin Infect Dis. (2023) 77:1552–60. doi: 10.1093/cid/ciad417

PubMed Abstract | Crossref Full Text | Google Scholar

24. Achar A, Myers R, and Ghosh C. Drug delivery challenges in brain disorders across the blood-brain barrier: novel methods and future considerations for improved therapy. Biomedicines. (2021) 9:1834. doi: 10.3390/biomedicines9121834

PubMed Abstract | Crossref Full Text | Google Scholar

25. Surles-Zeigler MC, Sincomb T, Gillespie TH, de Bono B, Bresnahan J, Mawe GM, et al. Extending and using anatomical vocabularies in the stimulating peripheral activity to relieve conditions project. Front Neuroinform. (2022) 16:819198. doi: 10.3389/fninf.2022.819198

PubMed Abstract | Crossref Full Text | Google Scholar

26. Lu L, Zhang Y, Tang X, Ge S, Wen H, Zeng J, et al. Evidence on acupuncture therapies is underused in clinical practice and health policy. BMJ. (2022) 376:e067475. doi: 10.1136/bmj-2021-067475

PubMed Abstract | Crossref Full Text | Google Scholar

27. Wang XY, Yu QQ, He W, Su YS, Zhang XN, Chen LZ, et al. From molecular pharmacy to electroceuticals: SPARC program and acupuncture research. Zhen ci yan jiu. (2019) 44:157–60. doi: 10.13702/j.1000-0607.190043

PubMed Abstract | Crossref Full Text | Google Scholar

28. Oh JE and Kim SN. Anti-Inflammatory Effects of Acupuncture at ST36 Point: A Literature Review in Animal Studies. Anti-Inflammatory Effects of Acupuncture at ST36 Point: A Literature Review in Animal Studies. . Front Immunol. (2022) 12:813748. doi: 10.3389/fimmu.2021.813748

PubMed Abstract | Crossref Full Text | Google Scholar

29. Li N, Guo Y, Gong Y, Zhang Y, Fan W, Yao K, et al. The anti-inflammatory actions and mechanisms of acupuncture from acupoint to target organs via neuro-immune regulation. J Inflammation Res. (2021) 14:7191–224. doi: 10.2147/JIR.S341581

PubMed Abstract | Crossref Full Text | Google Scholar

30. Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol. (2021) 85:355–75. doi: 10.1016/j.pneurobio.2008.05.004

PubMed Abstract | Crossref Full Text | Google Scholar

31. Chen T, Zhang WW, Chu YX, and Wang YQ. Acupuncture for pain management: molecular mechanisms of action. Am J Chin Med. (2020) 48:793–811. doi: 10.1142/S0192415X20500408

PubMed Abstract | Crossref Full Text | Google Scholar

32. Han D, Lu Y, Huang R, Yang Z, Peng G, Qiao Y, et al. Acupuncture for fibromyalgia: A review based on multidimensional evidence. Am J Chin Med. (2023) 51:249–77. doi: 10.1142/S0192415X23500143

PubMed Abstract | Crossref Full Text | Google Scholar

33. Luo D, Liu L, Zhang HM, Zhou YD, Zhou MF, Li JX, et al. Relationship between acupuncture and transient receptor potential vanilloid: Current and future directions. Front Mol Neurosci. (2022) 15:817738. doi: 10.3389/fnmol.2022.817738

PubMed Abstract | Crossref Full Text | Google Scholar

34. Cho E and Kim W. Effect of acupuncture on diabetic neuropathy: A narrative review. Int J Mol Sci. (2021) 22:8575. doi: 10.3390/ijms22168575

PubMed Abstract | Crossref Full Text | Google Scholar

35. Wang LN, Wang XZ, Li YJ, Li BR, Huang M, Wang XY, et al. Activation of subcutaneous mast cells in acupuncture points triggers analgesia. Cells. (2022) 11:809. doi: 10.3390/cells11050809

PubMed Abstract | Crossref Full Text | Google Scholar

36. Gao N, Li M, Wang W, Liu Z, and Guo Y. The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization. Front Mol Neurosci. (2024) 17:1400118. doi: 10.3389/fnmol.2024.1400118

PubMed Abstract | Crossref Full Text | Google Scholar

37. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, and Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. (1997) 389:816–24. doi: 10.1038/39807

PubMed Abstract | Crossref Full Text | Google Scholar

38. Caterina MJ. How do you feel? A warm and touching 2021 Nobel tribute. J Clin Invest. (2021) 131:e156587. doi: 10.1172/JCI156587

PubMed Abstract | Crossref Full Text | Google Scholar

39. Gao N, Li M, Wang W, Liu Z, and Guo Y. A bibliometrics analysis and visualization study of TRPV1 channel. Front Pharmacol. (2023) 14:1076921. doi: 10.3389/fphar.2023.1076921

PubMed Abstract | Crossref Full Text | Google Scholar

40. Zeng J, Lu Y, Chu H, Lu L, Chen Y, Ji K, et al. Research trends and frontier hotspots of TRPV1 based on bibliometric and visualization analyses. Heliyon. (2024) 10:e24153. doi: 10.1016/j.heliyon.2024.e24153

PubMed Abstract | Crossref Full Text | Google Scholar

41. Dou B, Li Y, Ma J, Xu Z, Fan W, Tian L, et al. Role of neuroimmune crosstalk in mediating the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain. Front Neurosci. (2021) 15:695670. doi: 10.3389/fnins.2021.695670

PubMed Abstract | Crossref Full Text | Google Scholar

42. Mezey E, Tóth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci U.S.A. (2000) 97:3655–60. doi: 10.1073/pnas.97.7.3655

PubMed Abstract | Crossref Full Text | Google Scholar

43. Venkatachalam K and Montell C. TRP channels. Annu Rev Biochem. (2007) 76:387–417. doi: 10.1146/annurev.biochem.75.103004.142819

PubMed Abstract | Crossref Full Text | Google Scholar

44. Han P, Korepanova AV, Vos MH, Moreland RB, Chiu ML, and Faltynek CR. Quantification of TRPV1 protein levels in rat tissues to understand its physiological roles. J Mol Neurosci. (2013) 50:23–32. doi: 10.1007/s12031-012-9849-7

PubMed Abstract | Crossref Full Text | Google Scholar

45. Tóth A, Boczán J, Kedei N, Lizanecz E, Bagi Z, Papp Z, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res Mol Brain Res. (2005) 135:162–8. doi: 10.1016/j.molbrainres.2004.12.003

PubMed Abstract | Crossref Full Text | Google Scholar

46. Brawek B and Garaschuk O. Monitoring in vivo function of cortical microglia. Cell calcium. (2017) 64:109–17. doi: 10.1016/j.ceca.2017.02.011

PubMed Abstract | Crossref Full Text | Google Scholar

47. Kölliker-Frers R, Udovin L, Otero-Losada M, Kobiec T, Herrera MI, Palacios J, et al. Neuroinflammation: an integrating overview of reactive-neuroimmune cell interactions in health and disease. Mediators Inflamm. (2021) 2021:9999146. doi: 10.1155/2021/9999146

PubMed Abstract | Crossref Full Text | Google Scholar

48. Zhao H, Lv Y, Xu J, Song X, Wang Q, Zhai X, et al. The activation of microglia by the complement system in neurodegenerative diseases. Ageing Res Rev. (2025) 104:102636. doi: 10.1016/j.arr.2024.102636

PubMed Abstract | Crossref Full Text | Google Scholar

49. Mirarchi A, Albi E, and Arcuri C. Microglia signatures: A cause or consequence of microglia-related brain disorders? Int J Mol Sci. (2024) 25:10951. doi: 10.3390/ijms252010951

PubMed Abstract | Crossref Full Text | Google Scholar

50. Liu Y, Wu L, Peng W, and Mao X. Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities. Ageing Res Rev. (2025) 104:102638. doi: 10.1016/j.arr.2024.102638

PubMed Abstract | Crossref Full Text | Google Scholar

51. Geloso MC, Zupo L, and Corvino V. Crosstalk between peripheral inflammation and brain: Focus on the responses of microglia and astrocytes to peripheral challenge. Neurochem Int. (2024) 180:105872. doi: 10.1016/j.neuint.2024.105872

PubMed Abstract | Crossref Full Text | Google Scholar

52. Conti P, Lauritano D, Caraffa A, Gallenga CE, Kritas SK, Ronconi G, et al. Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37. Eur J Pharmacol. (2020) 875:173035. doi: 10.1016/j.ejphar.2020.173035

PubMed Abstract | Crossref Full Text | Google Scholar

53. Obermeier B, Daneman R, and Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. (2013) 19:1584–96. doi: 10.1038/nm.3407

PubMed Abstract | Crossref Full Text | Google Scholar

54. Kwon DH, Zhang F, Suo Y, Bouvette J, Borgnia MJ, and Lee SY. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat Struct Mol Biol. (2021) 28:554–63. doi: 10.1038/s41594-021-00616-3

PubMed Abstract | Crossref Full Text | Google Scholar

55. Liao M, Cao E, Julius D, and Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. (2013) 504:107–12. doi: 10.1038/nature12822

PubMed Abstract | Crossref Full Text | Google Scholar

56. Wei XM, Yang QF, Tian JH, Yang H, Pan L, and Ding JJ. The function and gating mechanism of trpv1 channel and the application of its modulators in drug research and development. Prog Biochem Biophysics. (2023) 50:421–36. doi: 10.16476/j.pibb.2022.0198

Crossref Full Text | Google Scholar

57. Ogawa N, Kurokawa T, Fujiwara K, Polat OK, Badr H, Takahashi N, et al. Functional and structural divergence in human TRPV1 channel subunits by oxidative cysteine modification. J Biol Chem. (2016) 291:4197–210. doi: 10.1074/jbc.M115.700278

PubMed Abstract | Crossref Full Text | Google Scholar

58. Chen CC, Ke CH, Wu CH, Lee HF, Chao Y, Tsai MC, et al. Transient receptor potential vanilloid 1 inhibition reduces brain damage by suppressing neuronal apoptosis after intracerebral hemorrhage. Brain Pathol. (2024) 34:e13244. doi: 10.1111/bpa.13244

PubMed Abstract | Crossref Full Text | Google Scholar

59. González A, Sáez CA, Morales B, and Moenne A. Copper-induced activation of TRP channels promotes extracellular calcium entry and activation of CaMK, PKA, PKC, PKG and CBLPK leading to increased expression of antioxidant enzymes in Ectocarpus siliculosus. Plant Physiol Biochem. (2018) 126:106–16. doi: 10.1016/j.plaphy.2018.02.032

PubMed Abstract | Crossref Full Text | Google Scholar

60. Xu YP, Zhang JW, Li L, Ye ZY, Zhang Y, Gao X, et al. Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons. Neurosci Lett. (2012) 517:30–5. doi: 10.1016/j.neulet.2012.04.011

PubMed Abstract | Crossref Full Text | Google Scholar

61. Stratiievska A, Nelson S, Senning EN, Lautz JD, Smith SE, and Gordon SE. Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. Elife. (2018) 7:e38869. doi: 10.7554/eLife.38869

PubMed Abstract | Crossref Full Text | Google Scholar

62. Liu B, Ma W, Ryu S, and Qin F. Inhibitory modulation of distal C-terminal on protein kinase C-dependent phospho-regulation of rat TRPV1 receptors. J Physiol. (2004) 560:627–38. doi: 10.1113/jphysiol.2004.069054

PubMed Abstract | Crossref Full Text | Google Scholar

63. Zhang X, Li L, and McNaughton PA. Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron. (2008) 59:450–61. doi: 10.1016/j.neuron.2008.05.015

PubMed Abstract | Crossref Full Text | Google Scholar

64. Lau SY, Procko E, and Gaudet R. Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J Gen Physiol. (2012) 140:541–55. doi: 10.1085/jgp.201210810

PubMed Abstract | Crossref Full Text | Google Scholar

65. Goswami C, Dreger M, Jahnel R, Bogen O, Gillen C, and Hucho F. Identification and characterization of a Ca2+ -sensitive interaction of the vanilloid receptor TRPV1 with tubulin. J Neurochem. (2004) 91:1092–103. doi: 10.1111/j.1471-4159.2004.02795.x

PubMed Abstract | Crossref Full Text | Google Scholar

66. Wang Y, Gao Y, Tian Q, Deng Q, Wang Y, Zhou T, et al. TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain. Nat Commun. (2018) 9:1529. doi: 10.1038/s41467-018-05022-w

PubMed Abstract | Crossref Full Text | Google Scholar

67. Morales-Lázaro SL and Rosenbaum T. A painful link between the TRPV1 channel and lysophosphatidic acid. Life Sci. (2015) 125:15–24. doi: 10.1016/j.lfs.2014.10.004

PubMed Abstract | Crossref Full Text | Google Scholar

68. Kim SR, Kim SU, Oh U, and Jin BK. Transient receptor potential vanilloid subtype 1 mediates microglial cell death in vivo and in vitro via Ca2+-mediated mitochondrial damage and cytochrome c release. J Immunol. (2006) 177:4322–9. doi: 10.4049/jimmunol.177.7.4322

PubMed Abstract | Crossref Full Text | Google Scholar

69. Pallarés-Moratalla C and Bergers G. The ins and outs of microglial cells in brain health and disease. Front Immunol. (2024) 15:1305087. doi: 10.3389/fimmu.2024.1305087

PubMed Abstract | Crossref Full Text | Google Scholar

70. Aguzzi A, Barres BA, and Bennett ML. Microglia: scapegoat, saboteur, or something else? Science. (2013) 339:156–61. doi: 10.1126/science.1227901

PubMed Abstract | Crossref Full Text | Google Scholar

71. Valiukas Z, Tangalakis K, Apostolopoulos V, and Feehan J. Microglial activation states and their implications for Alzheimer’s Disease. J Prev Alzheimers Dis. (2025) 12:100013. doi: 10.1016/j.tjpad.2024.100013

PubMed Abstract | Crossref Full Text | Google Scholar

72. Schilling T and Eder C. Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J Cell Physiol. (2011) 226:3295–302. doi: 10.1002/jcp.22675

PubMed Abstract | Crossref Full Text | Google Scholar

73. Joseph DJ, Choudhury P, and Macdermott AB. An in vitro assay system for studying synapse formation between nociceptive dorsal root ganglion and dorsal horn neurons. J Neurosci Methods. (2010) 189:197–204. doi: 10.1016/j.jneumeth.2010.04.002

PubMed Abstract | Crossref Full Text | Google Scholar

74. Cernit V, Sénécal J, Othman R, and Couture R. Reciprocal regulatory interaction between TRPV1 and kinin B1 receptor in a rat neuropathic pain model. Int J Mol Sci. (2020) 21:821. doi: 10.3390/ijms21030821

PubMed Abstract | Crossref Full Text | Google Scholar

75. Wilkerson JL, Alberti LB, Thakur GA, Makriyannis A, and Milligan ED. Peripherally administered cannabinoid receptor 2 (CB2R) agonists lose anti-allodynic effects in TRPV1 knockout mice, while intrathecal administration leads to anti-allodynia and reduced GFAP, CCL2 and TRPV1 expression in the dorsal spinal cord and DRG. Brain Res. (2022) 1774:147721. doi: 10.1016/j.brainres.2021.147721

PubMed Abstract | Crossref Full Text | Google Scholar

76. Shibata Y, Matsumoto Y, Kohno K, Nakashima Y, and Tsuda M. Microgliosis in the spinal dorsal horn early after peripheral nerve injury is associated with damage to primary afferent Aβ-fibers. Cells. (2025) 14:666. doi: 10.3390/cells14090666

PubMed Abstract | Crossref Full Text | Google Scholar

77. Fang K, Lu P, Cheng W, and Yu B. Kilohertz high-frequency electrical stimulation ameliorate hyperalgesia by modulating transient receptor potential vanilloid-1 and N-methyl-D-aspartate receptor-2B signaling pathways in chronic constriction injury of sciatic nerve mice. Mol Pain. (2024) 20:17448069231225810. doi: 10.1177/17448069231225810

PubMed Abstract | Crossref Full Text | Google Scholar

78. Baba K, Kawasaki M, Nishimura H, Suzuki H, Matsuura T, Fujitani T, et al. Heat hypersensitivity is attenuated with altered expression level of spinal astrocytes after sciatic nerve injury in TRPV1 knockout mice. Neurosci Res. (2021) 170:273–83. doi: 10.1016/j.neures.2020.12.007

PubMed Abstract | Crossref Full Text | Google Scholar

79. Raboune S, Stuart JM, Leishman E, Takacs SM, Rhodes B, Basnet A, et al. Novel endogenous N-acyl amides activate TRPV1–4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation. Front Cell Neurosci. (2014) 8:195. doi: 10.3389/fncel.2014.00195

PubMed Abstract | Crossref Full Text | Google Scholar

80. Wang ZV and Scherer PE. Adiponectin, the past two decades. J Mol Cell Biol. (2016) 8:93–100. doi: 10.1093/jmcb/mjw011

PubMed Abstract | Crossref Full Text | Google Scholar

81. Chabry J, Nicolas S, Cazareth J, Murris E, Guyon A, Glaichenhaus N, et al. Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior. Brain Behav Immun. (2015) 50:275–87. doi: 10.1016/j.bbi.2015.07.018

PubMed Abstract | Crossref Full Text | Google Scholar

82. Sun L, Li H, Tai LW, Gu P, and Cheung CW. Adiponectin regulates thermal nociception in a mouse model of neuropathic pain. Br J Anaesth. (2018) 120:1356–67. doi: 10.1016/j.bja.2018.01.016

PubMed Abstract | Crossref Full Text | Google Scholar

83. Giordano C, Cristino L, Luongo L, Siniscalco D, Petrosino S, Piscitelli F, et al. TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception. Cereb Cortex. (2012) 22:2495–518. doi: 10.1093/cercor/bhr328

PubMed Abstract | Crossref Full Text | Google Scholar

84. Marrone MC, Morabito A, Giustizieri M, Chiurchiù V, Leuti A, Mattioli M, et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat Commun. (2017) 8:15292. doi: 10.1038/ncomms15292

PubMed Abstract | Crossref Full Text | Google Scholar

85. Jeske NA, Diogenes A, Ruparel NB, Fehrenbacher JC, Henry M, Akopian AN, et al. A-kinase anchoring protein mediates TRPV1 thermal hyperalgesia through PKA phosphorylation of TRPV1. Pain. (2008) 138:604–16. doi: 10.1016/j.pain.2008.02.022

PubMed Abstract | Crossref Full Text | Google Scholar

86. Dubin AE, Schmidt M, Mathur J, Petrus MJ, Xiao B, Coste B, et al. Inflammatory signals enhance piezo2-mediated mechanosensitive currents. Cell Rep. (2012) 2:511–7. doi: 10.1016/j.celrep.2012.07.014

PubMed Abstract | Crossref Full Text | Google Scholar

87. Gu Y, Li G, and Huang LM. Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1-mediated hyperalgesia. Pain. (2018) 159:2383–93. doi: 10.1097/j.pain.0000000000001346

PubMed Abstract | Crossref Full Text | Google Scholar

88. Wang S, Joseph J, Ro JY, and Chung MK. Modality-specific mechanisms of protein kinase C-induced hypersensitivity of TRPV1: S800 is a polymodal sensitization site. Pain. (2015) 156:931–41. doi: 10.1097/j.pain.0000000000000134

PubMed Abstract | Crossref Full Text | Google Scholar

89. Vetter I, Cheng W, Peiris M, Wyse BD, Roberts-Thomson SJ, Zheng J, et al. Rapid, opioid-sensitive mechanisms involved in transient receptor potential vanilloid 1 sensitization. J Biol Chem. (2008) 283:19540–50. doi: 10.1074/jbc.M707865200

PubMed Abstract | Crossref Full Text | Google Scholar

90. Joseph J, Qu L, Wang S, Kim M, Bennett D, Ro J, et al. Phosphorylation of TRPV1 S801 contributes to modality-specific hyperalgesia in mice. J Neurosci. (2019) 39:9954–66. doi: 10.1523/JNEUROSCI.1064-19.2019

PubMed Abstract | Crossref Full Text | Google Scholar

91. Kim Y, Je MA, Jeong M, Kwon H, Jang A, Kim J, et al. Upregulation of NGF/trkA-related proteins in dorsal root ganglion of paclitaxel-induced peripheral neuropathy animal model. J Pain Res. (2024) 17:3919–32. doi: 10.2147/JPR.S470671

PubMed Abstract | Crossref Full Text | Google Scholar

92. Lu CC, Lin CY, Lu YY, Tsai HP, Lin CL, and Wu CH. CDDO regulates central and peripheral sensitization to attenuate post-herpetic neuralgia by targeting TRPV1/PKC-δ/p-Akt signals. J Cell Mol Med. (2024) 28:e18131. doi: 10.1111/jcmm.18131

PubMed Abstract | Crossref Full Text | Google Scholar

93. Zhang X, Peng L, and Liu D. Pregabalin alleviates neuropathic pain via inhibition of the PKCϵ/TRPV1 pathway. Neurosci Lett. (2022) 766:136348. doi: 10.1016/j.neulet.2021.136348

PubMed Abstract | Crossref Full Text | Google Scholar

94. Hong HK, Ma Y, and Xie H. TRPV1 and spinal astrocyte activation contribute to remifentanil-induced hyperalgesia in rats. Neuroreport. (2019) 30:1095–101. doi: 10.1097/WNR.0000000000001329

PubMed Abstract | Crossref Full Text | Google Scholar

95. Rossi S, Motta C, Studer V, Macchiarulo G, Volpe E, Barbieri F, et al. Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53. Mol Neurodegener. (2014) 9:56. doi: 10.1186/1750-1326-9-56

PubMed Abstract | Crossref Full Text | Google Scholar

96. Yue J and López JM. Understanding MAPK signaling pathways in apoptosis. Int J Mol Sci. (2020) 21:2346. doi: 10.3390/ijms21072346

PubMed Abstract | Crossref Full Text | Google Scholar

97. Kino T, Tomori T, Abutarboush R, Castri P, Chen Y, Lenz FA, et al. Effect of N-arachidonoyl-l-serine on human cerebromicrovascular endothelium. Biochem Biophys Rep. (2016) 8:254–60. doi: 10.1016/j.bbrep.2016.09.002

PubMed Abstract | Crossref Full Text | Google Scholar

98. Shirakawa H, Yamaoka T, Sanpei K, Sasaoka H, Nakagawa T, and Kaneko S. TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons. Biochem Biophys Res Commun. (2008) 377:1211–5. doi: 10.1016/j.bbrc.2008.10.152

PubMed Abstract | Crossref Full Text | Google Scholar

99. Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, et al. Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. (2007) 102:977–90. doi: 10.1111/j.1471-4159.2007.04582.x

PubMed Abstract | Crossref Full Text | Google Scholar

100. Miyake T, Shirakawa H, Nakagawa T, and Kaneko S. Activation of mitochondrial transient receptor potential vanilloid 1 channel contributes to microglial migration. Glia. (2015) 63:1870–82. doi: 10.1002/glia.22854

PubMed Abstract | Crossref Full Text | Google Scholar

101. Zhang K, Qin Z, Chen J, Guo G, Jiang X, Wang F, et al. TRPV1 modulated NLRP3 inflammasome activation via calcium in experimental subarachnoid hemorrhage. Aging (Albany NY). (2024) 16:1096–110. doi: 10.18632/aging.205379

PubMed Abstract | Crossref Full Text | Google Scholar

102. Chen Y and Yu Y. Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation. J Neuroinflammation. (2023) 20:165. doi: 10.1186/s12974-023-02853-3

PubMed Abstract | Crossref Full Text | Google Scholar

103. Edwards G, Zhao J 3rd, Dash PK, Soto C, and Moreno-Gonzalez I. Traumatic brain injury induces tau aggregation and spreading. J Neurotrauma. (2020) 37:80–92. doi: 10.1089/neu.2018.6348

PubMed Abstract | Crossref Full Text | Google Scholar

104. Yu F, Iacono D, Perl DP, Lai C, Gill J, Le TQ, et al. Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice. Acta Neuropathol. (2023) 146:585–610. doi: 10.1007/s00401-023-02622-9

PubMed Abstract | Crossref Full Text | Google Scholar

105. Corrigan F, Cernak I, McAteer K, Hellewell SC, Rosenfeld JV, Turner RJ, et al. NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury. Sci Rep. (2021) 1:8861. doi: 10.1038/s41598-021-88237-0

PubMed Abstract | Crossref Full Text | Google Scholar

106. Yang DX, Jing Y, Liu YL, Xu ZM, Yuan F, Wang ML, et al. Inhibition of transient receptor potential vanilloid 1 attenuates blood-brain barrier disruption after traumatic brain injury in mice. J Neurotrauma. (2019) 36:1279–90. doi: 10.1089/neu.2018.5942

PubMed Abstract | Crossref Full Text | Google Scholar

107. van den Heuvel AP, de Vries-Smits AM, van Weeren PC, Dijkers PF, de Bruyn KM, Riedl JA, et al. Binding of protein kinase B to the plakin family member periplakin. J Cell Sci. (2002) 115:3957–66. doi: 10.1089/neu.2018.5942

PubMed Abstract | Crossref Full Text | Google Scholar

108. Ling X and Wang W. A-80426 suppresses CFA-induced inflammatory pain by suppressing TRPV1 activity via NFκB and PI3K pathways in mice. Clinics (Sao Paulo). (2023) 78:100213. doi: 10.1016/j.clinsp.2023.100213

PubMed Abstract | Crossref Full Text | Google Scholar

109. Zhang Z, Leng Z, Kang L, Yan X, Shi J, Ji Y, et al. Alcohol inducing macrophage M2b polarization in colitis by modulating the TRPV1-MAPK/NF-κB pathways. Phytomedicine. (2024) 130:155580. doi: 10.1016/j.phymed.2024.155580

PubMed Abstract | Crossref Full Text | Google Scholar

110. Liu Y, Liu Y, Jin H, Cong P, Zhang Y, Tong C, et al. Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway. Brain Res. (2017) 1670:201–7. doi: 10.1016/j.brainres.2017.06.025

PubMed Abstract | Crossref Full Text | Google Scholar

111. Dos-Santos-Pereira M, da-Silva CA, Guimarães FS, and Del-Bel E. Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: Possible mechanism of action. Neurobiol Dis. (2016) 94:179–95. doi: 10.1016/j.nbd.2016.06.013

PubMed Abstract | Crossref Full Text | Google Scholar

112. Chen Y, Geis C, and Sommer C. Activation of TRPV1 contributes to morphine tolerance: involvement of the mitogen-activated protein kinase signaling pathway. J Neurosci. (2008) 28:5836–45. doi: 10.1523/JNEUROSCI.4170-07.2008

PubMed Abstract | Crossref Full Text | Google Scholar

113. Hong SI, Nguyen TL, Ma SX, Kim HC, Lee SY, and Jang CG. TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens. Behav Brain Res. (2017) 334:26–33. doi: 10.1016/j.bbr.2017.07.017

PubMed Abstract | Crossref Full Text | Google Scholar

114. Ma SX, Kwon SH, Seo JY, Hwang JY, Hong SI, Kim HC, et al. Impairment of opiate-mediated behaviors by the selective TRPV1 antagonist SB366791. Addict Biol. (2017) 22:1817–28. doi: 10.1111/adb.12460

PubMed Abstract | Crossref Full Text | Google Scholar

115. Nguyen TL, Kwon SH, Hong SI, Ma SX, Jung YH, Hwang JY, et al. Transient receptor potential vanilloid type 1 channel may modulate opioid reward. Neuropsychopharmacology. (2014) 39:2414–22. doi: 10.1038/npp.2014.90

PubMed Abstract | Crossref Full Text | Google Scholar

116. Yang H, Andersson U, and Brines M. Neurons are a primary driver of inflammation via release of HMGB1. Cells. (2021) 10:2791. doi: 10.3390/cells10102791

PubMed Abstract | Crossref Full Text | Google Scholar

117. Acter S and Lin Q. S100 proteins as a key immunoregulatory mechanism for NLRP3 inflammasome. Front Immunol. (2025) 16:1663547. doi: 10.3389/fimmu.2025.1663547

PubMed Abstract | Crossref Full Text | Google Scholar

118. Liu Z, Li M, Zhang L, Shi X, Liao T, Jie L, et al. NGF signaling exacerbates KOA peripheral hyperalgesia via the increased TRPV1-labeled synovial sensory innervation in KOA rats. Pain Res Manage. (2024) 2024:1552594. doi: 10.1155/2024/1552594

PubMed Abstract | Crossref Full Text | Google Scholar

119. Bestall SM, Hulse RP, Blackley Z, Swift M, Ved N, Paton K, et al. Sensory neuronal sensitisation occurs through HMGB-1-RAGE and TRPV1 in high-glucose conditions. J Cell Sci. (2018) 131:jcs215939. doi: 10.1242/jcs.215939

PubMed Abstract | Crossref Full Text | Google Scholar

120. Huang WX, Yu F, Sanchez RM, Liu YQ, Min JW, Hu JJ, et al. TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain. Brain Behav Immun. (2015) 48:68–77. doi: 10.1016/j.bbi.2015.01.017

PubMed Abstract | Crossref Full Text | Google Scholar

121. Tsai ST, Wei TH, Yang YW, Lu MK, San S, Tsai CH, et al. Transient receptor potential V1 modulates neuroinflammation in Parkinson’s disease dementia: Molecular implications for electroacupuncture and rivastigmine. Iran J Basic Med Sci. (2021) 24:1336–45. doi: 10.22038/IJBMS.2021.56156.12531

PubMed Abstract | Crossref Full Text | Google Scholar

122. Kong W, Wang X, Yang X, Huang W, Han S, Yin J, et al. Activation of TRPV1 contributes to recurrent febrile seizures via inhibiting the microglial M2 phenotype in the immature brain. Front Cell Neurosci. (2019) 13:442. doi: 10.3389/fncel.2019.00442

PubMed Abstract | Crossref Full Text | Google Scholar

123. Xu Q, Zhao B, Ye Y, Li Y, Zhang Y, Xiong X, et al. Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J Neuroinflammation. (2021) 18:123. doi: 10.1186/s12974-021-02137-8

PubMed Abstract | Crossref Full Text | Google Scholar

124. Zhao W, Chen M, Yu X, Zhong H, Hao S, Liu S, et al. 4-Methylesculetin attenuates inflammatory pain via inhibition of Sp1-TRPV1 and inflammation related signaling pathways. Int Immunopharmacol. (2025) 152:114379. doi: 10.1016/j.intimp.2025.114379

PubMed Abstract | Crossref Full Text | Google Scholar

125. Yin C, Lyu Q, Dong Z, Liu B, Zhang K, Liu Z, et al. Well-defined alginate oligosaccharides ameliorate joint pain and inflammation in a mouse model of gouty arthritis. Theranostics. (2024) 14:3082–103. doi: 10.7150/thno.95611

PubMed Abstract | Crossref Full Text | Google Scholar

126. Ahn JH, Sung JY, McAvoy T, Nishi A, Janssens V, Goris J, et al. The B’’/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A. Proc Natl Acad Sci U S A. (2007) 104:9876–81. doi: 10.1073/pnas.0703589104

PubMed Abstract | Crossref Full Text | Google Scholar

127. Stutz A, Kolbe CC, Stahl R, Horvath GL, Franklin BS, van Ray O, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med. (2017) 214:1725–36. doi: 10.1084/jem.20160933

PubMed Abstract | Crossref Full Text | Google Scholar

128. Zhang Y, Hou B, Liang P, Lu X, Wu Y, Zhang X, et al. TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia. Cell Death Dis. (2021) 12:1159. doi: 10.1038/s41419-021-04450-9

PubMed Abstract | Crossref Full Text | Google Scholar

129. Salminen A. Redox-sensitive high mobility group box 1 (HMGB1) is a multifunctional regulator of cellular senescence, inflammation, and immunosuppression: impact on the aging process. Ageing Res Rev. (2025) 22:102926. doi: 10.1016/j.arr.2025.102926

PubMed Abstract | Crossref Full Text | Google Scholar

130. Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, and Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol. (2024) 98:1323–67. doi: 10.1007/s00204-024-03696-4

PubMed Abstract | Crossref Full Text | Google Scholar

131. Awad-Igbaria Y, Ben-Menashe A, Sakas R, Edelman D, Fishboom T, Shamir A, et al. Novel insight into TRPV1-induced mitochondrial dysfunction in neuropathic pain. Brain. (2025) 148:2563–78. doi: 10.1093/brain/awaf044

PubMed Abstract | Crossref Full Text | Google Scholar

132. Özdemir ÜS, Nazıroğlu M, Şenol N, and Ghazizadeh V. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol. (2016) 53:3540–51. doi: 10.1007/s12035-015-9292-1

PubMed Abstract | Crossref Full Text | Google Scholar

133. Zhu Z, Lu W, Fang Y, Zhuang J, Song J, Jiang M, et al. Galanin regulates M1/M2 polarization of microglia after spinal cord injury through TRPV1/Ca2+/CaMKII/NRF2 signaling pathway. Int Immunopharmacol. (2025) 164:115330. doi: 10.1016/j.intimp.2025.115330

PubMed Abstract | Crossref Full Text | Google Scholar

134. Khan A, Wang F, Shal B, Khan AU, Zahra SS, Haq IU, et al. Anti-neuropathic pain activity of Ajugarin-I via activation of Nrf2 signaling and inhibition of TRPV1/TRPM8 nociceptors in STZ-induced diabetic neuropathy. Pharmacol Res. (2022) 183:106392. doi: 10.1016/j.phrs.2022.106392

PubMed Abstract | Crossref Full Text | Google Scholar

135. Ozdamar Unal G, Demirdas A, Nazıroglu M, and Ovey IS. Agomelatine attenuates calcium signaling and apoptosis via the inhibition of TRPV1 channel in the hippocampal neurons of rats with chronic mild stress depression model. Behav Brain Res. (2022) 434:114033. doi: 10.1016/j.bbr.2022.114033

PubMed Abstract | Crossref Full Text | Google Scholar

136. Luan K, Rosales JL, and Lee KY. Viewpoint: Crosstalks between neurofibrillary tangles and amyloid plaque formation. Ageing Res Rev. (2013) 12:174–81. doi: 10.1016/j.arr.2012.06.002

PubMed Abstract | Crossref Full Text | Google Scholar

137. Bojarski L, Herms J, and Kuznicki J. Calcium dysregulation in Alzheimer’s disease. Neurochem Int. (2008) 52:621–33. doi: 10.1016/j.neuint.2007.10.002

PubMed Abstract | Crossref Full Text | Google Scholar

138. Cascella R and Cecchi C. Calcium dyshomeostasis in alzheimer’s disease pathogenesis. Int J Mol Sci. (2021) 22:4914. doi: 10.3390/ijms22094914

PubMed Abstract | Crossref Full Text | Google Scholar

139. Hanger DP, Anderton BH, and Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. (2009) 15:112–9. doi: 10.1016/j.molmed.2009.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

140. Wang X, Bian Y, Wong CTT, Lu JH, and Lee SM. TRPV1 modulator ameliorates alzheimer-like amyloid-β Neuropathology via akt/gsk3β-mediated nrf2 activation in the neuro-2a/APP cell model. Oxid Med Cell Longev. (2022) 2022:1544244. doi: 10.1155/2022/1544244

PubMed Abstract | Crossref Full Text | Google Scholar

141. Kahya MC, Nazıroğlu M, and Övey İS. Modulation of diabetes-induced oxidative stress, apoptosis, and ca2+ Entry through TRPM2 and TRPV1 channels in dorsal root ganglion and hippocampus of diabetic rats by melatonin and selenium. Mol Neurobiol. (2017) 54:2345–60. doi: 10.1007/s12035-016-9727-3

PubMed Abstract | Crossref Full Text | Google Scholar

142. Jiao W, Lin J, Deng Y, Ji Y, Liang C, Wei S, et al. The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms. J Neuroinflammation. (2025) 22:10. doi: 10.1186/s12974-024-03312-3

PubMed Abstract | Crossref Full Text | Google Scholar

143. Duan M, Xu Y, Li Y, Feng H, and Chen Y. Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke. J Neuroinflammation. (2024) 21:102. doi: 10.1186/s12974-024-03101-y

PubMed Abstract | Crossref Full Text | Google Scholar

144. Huang Y, Chen SR, and Pan HL. Calcineurin regulates synaptic plasticity and nociceptive transmission at the spinal cord level. Neuroscientist. (2022) 28:628–38. doi: 10.1177/10738584211046888

PubMed Abstract | Crossref Full Text | Google Scholar

145. Yang F, Guo J, Sun WL, Liu FY, Cai J, Xing GG, et al. The induction of long-term potentiation in spinal dorsal horn after peripheral nociceptive stimulation and contribution of spinal TRPV1 in rats. Neuroscience. (2014) 269:59–66. doi: 10.1016/j.neuroscience.2014.03.037

PubMed Abstract | Crossref Full Text | Google Scholar

146. Kang SY, Seo SY, Bang SK, Cho SJ, Choi KH, and Ryu Y. Inhibition of spinal TRPV1 reduces NMDA receptor 2B phosphorylation and produces anti-nociceptive effects in mice with inflammatory pain. Int J Mol Sci. (2021) 22:11177. doi: 10.3390/ijms222011177

PubMed Abstract | Crossref Full Text | Google Scholar

147. Ngoc KH, Kecskés A, Kepe E, Nabi L, Keeble J, Borbély É, et al. Expression of the Transient Receptor Potential Vanilloid 1 ion channel in the supramammillary nucleus and the antidepressant effects of its antagonist AMG9810 in mice. Eur Neuropsychopharmacol. (2023) 73:96–107. doi: 10.1016/j.euroneuro.2023.04.017

PubMed Abstract | Crossref Full Text | Google Scholar

148. Sun FJ, Guo W, Zheng DH, Zhang CQ, Li S, Liu SY, et al. Increased expression of TRPV1 in the cortex and hippocampus from patients with mesial temporal lobe epilepsy. J Mol Neurosci. (2013) 49:182–93. doi: 10.1007/s12031-012-9878-2

PubMed Abstract | Crossref Full Text | Google Scholar

149. Zhang X, Wang D, Zhang B, Zhu J, Zhou Z, and Cui L. Regulation of microglia by glutamate and its signal pathway in neurodegenerative diseases. Drug Discov Today. (2020) 25:1074–85. doi: 10.1016/j.drudis.2020.04.001

PubMed Abstract | Crossref Full Text | Google Scholar

150. Shoudai K, Peters JH, McDougall SJ, Fawley JA, and Andresen MC. Thermally active TRPV1 tonically drives central spontaneous glutamate release. J Neurosci. (2010) 30:14470–5. doi: 10.1523/JNEUROSCI.2557-10.2010

PubMed Abstract | Crossref Full Text | Google Scholar

151. Alter BJ and Gereau RW,4. Hotheaded: TRPV1 as mediator of hippocampal synaptic plasticity. Neuron. (2008) 57:629–31. doi: 10.1016/j.neuron.2008.02.023

PubMed Abstract | Crossref Full Text | Google Scholar

152. Chu HY, Yang Z, Zhao B, Jin GZ, Hu GY, and Zhen X. Activation of phosphatidylinositol-linked D1-like receptors increases spontaneous glutamate release in rat somatosensory cortical neurons in vitro. Brain Res. (2010) 1343:20–7. doi: 10.1016/j.brainres.2010.04.043

PubMed Abstract | Crossref Full Text | Google Scholar

153. Musella A, De Chiara V, Rossi S, Prosperetti C, Bernardi G, Maccarrone M, et al. TRPV1 channels facilitate glutamate transmission in the striatum. Mol Cell Neurosci. (2009) 40:89–97. doi: 10.1016/j.mcn.2008.09.001

PubMed Abstract | Crossref Full Text | Google Scholar

154. de Novellis V, Vita D, Gatta L, Luongo L, Bellini G, De Chiaro M, et al. The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats. Mol Pain. (2011) 7:7. doi: 10.1186/1744-8069-7-7

PubMed Abstract | Crossref Full Text | Google Scholar

155. Marin-Castañeda LA, Pacheco Aispuro G, Gonzalez-Garibay G, Martínez Zamora CA, Romo-Parra H, Rubio-Osornio M, et al. Interplay of epilepsy and long-term potentiation: implications for memory. Front Neurosci. (2025) 18:1451740. doi: 10.3389/fnins.2024.1451740

PubMed Abstract | Crossref Full Text | Google Scholar

156. Manna SSS. Dual effects of anandamide in the antiepileptic activity of diazepam in pentylenetetrazole-induced seizures in mice. Behav Pharmacol. (2022) 33:527–41. doi: 10.1097/FBP.0000000000000700

PubMed Abstract | Crossref Full Text | Google Scholar

157. Socała K, Jakubiec M, Abram M, Mlost J, Starowicz K, Kamiński RM, et al. TRPV1 channel in the pathophysiology of epilepsy and its potential as a molecular target for the development of new antiseizure drug candidates. Prog Neurobiol. (2024) 240:102634. doi: 10.1097/FBP.0000000000000700

PubMed Abstract | Crossref Full Text | Google Scholar

158. Fu M, Xie Z, and Zuo H. TRPV1: a potential target for antiepileptogenesis. Med Hypotheses. (2009) 73:100–2. doi: 10.1016/j.mehy.2009.01.005

PubMed Abstract | Crossref Full Text | Google Scholar

159. Gibson HE A, Edwards JG, Page RS, Van Hook MJ, and Kauer JA. TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron. (2008) 57:746–59. doi: 10.1016/j.neuron.2007.12.027

PubMed Abstract | Crossref Full Text | Google Scholar

160. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F, et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci. (2007) 27:832–9. doi: 10.1523/JNEUROSCI.3303-06.2007

PubMed Abstract | Crossref Full Text | Google Scholar

161. Marinelli S, Marrone MC, Di Domenico M, and Marinelli S. Endocannabinoid signaling in microglia. Glia. (2023) 71:71–90. doi: 10.1002/glia.24281

PubMed Abstract | Crossref Full Text | Google Scholar

162. Abbruzzese M, Bellodi L, and Scarone S. Frontal lobe dysfunction in schizophrenia and obsessive-compulsive disorder: a neuropsychological study. Brain Cogn. (1995) 27:202–12. doi: 10.1006/brcg.1995.1017

PubMed Abstract | Crossref Full Text | Google Scholar

163. Bishop SJ. Neurocognitive mechanisms of anxiety: an integrative account. Trends Cognit Sci. (2007) 11:307–16. doi: 10.1016/j.tics.2007.05.008

PubMed Abstract | Crossref Full Text | Google Scholar

164. Mathew SJ, Price RB, and Charney DS. Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am J Med Genet C Semin Med Genet. (2008) 148C:89–98. doi: 10.1002/ajmg.c.30172

PubMed Abstract | Crossref Full Text | Google Scholar

165. Bandler R, Keay KA, Floyd N, and Price J. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull. (2000) 53:95–104. doi: 10.1016/s0361-9230(00)00313-0

PubMed Abstract | Crossref Full Text | Google Scholar

166. Knight EJ, Min HK, Hwang SC, Marsh MP, Paek S, Kim I, et al. Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. PloS One. (2013) 8:e56640. doi: 10.1371/journal.pone.0056640

PubMed Abstract | Crossref Full Text | Google Scholar

167. Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, and Di Marzo V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. (2006) 139:1405–15. doi: 10.1016/j.neuroscience.2006.02.074

PubMed Abstract | Crossref Full Text | Google Scholar

168. Aguiar DC, Terzian AL, Guimarães FS, and Moreira FA. Anxiolytic-like effects induced by blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the medial prefrontal cortex of rats. Psychopharmacology. (2009) 205:217–25. doi: 10.1007/s00213-009-1532-5

PubMed Abstract | Crossref Full Text | Google Scholar

169. Uliana DL, Antero LS, Borges-Assis AB, Rosa J, Vila-Verde C, Lisboa SF, et al. Differential modulation of the contextual conditioned emotional response by CB1 and TRPV1 receptors in the ventromedial prefrontal cortex: Possible involvement of NMDA/nitric oxide-related mechanisms. J Psychopharmacol. (2020) 34:1043–55. doi: 10.1177/0269881120928201

PubMed Abstract | Crossref Full Text | Google Scholar

170. Pardo-García TR, Yusif-Rodriguez N, Yudowski G, and Maldonado-Vlaar CS. Blockade of the endovanilloid receptor, TRPV1, and of the endocannabinoid enzyme, FAAH, within the nucleus accumbens shell elicits anxiolytic-like effects in male rats. Neurosci Lett. (2020) 732:135023. doi: 10.1016/j.neulet.2020.135023

PubMed Abstract | Crossref Full Text | Google Scholar

171. Morgese MG, Cassano T, Cuomo V, and Giuffrida A. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson’s disease: role of CB(1) and TRPV1 receptors. Exp Neurol. (2007) 208:110–9. doi: 10.1016/j.expneurol.2007.07.021

PubMed Abstract | Crossref Full Text | Google Scholar

172. Razavinasab M, Shamsizadeh A, Shabani M, Nazeri M, Allahtavakoli M, Asadi-Shekaari M, et al. Pharmacological blockade of TRPV1 receptors modulates the effects of 6-OHDA on motor and cognitive functions in a rat model of Parkinson’s disease. Fundam Clin Pharmacol. (2013) 27:632–40. doi: 10.1111/fcp.12015

PubMed Abstract | Crossref Full Text | Google Scholar

173. Terzian AL, Aguiar DC, Guimarães FS, and Moreira FA. Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray. Eur Neuropsychopharmacol. (2009) 19:188–95. doi: 10.1016/j.euroneuro.2008.11.004

PubMed Abstract | Crossref Full Text | Google Scholar

174. Kim J, Lee S, Kim J, Ham S, Park JHY, Han S, et al. Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer’s disease. Hum Mol Genet. (2020) 29:228–37. doi: 10.1093/hmg/ddz276

PubMed Abstract | Crossref Full Text | Google Scholar

175. Aguiar DC, Moreira FA, Terzian AL, Fogaça MV, Lisboa SF, Wotjak CT, et al. Modulation of defensive behavior by Transient Receptor Potential Vanilloid Type-1 (TRPV1) channels. Neurosci Biobehav Rev. (2014) 46(3):418–28. doi: 10.1016/j.neubiorev.2014.03.026

PubMed Abstract | Crossref Full Text | Google Scholar

176. Bertacchini GL, Sonego AB, Lisboa SF, Lagatta DC, and Resstel LBM. The expression of contextual fear conditioning involves the dorsal hippocampus TRPV1 receptor interacting with the NMDA/NO/cGMP signalling pathway. Br J Pharmacol. (2025) 182:1107–20. doi: 10.1111/bph.17384

PubMed Abstract | Crossref Full Text | Google Scholar

177. Clarke TC, Black LI, Stussman BJ, Barnes PM, and Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Rep. (2015) 2015:1–16.

PubMed Abstract | Google Scholar

178. Zhang Y, Lao L, Chen H, and Ceballos R. Acupuncture use among american adults: what acupuncture practitioners can learn from national health interview survey 2007? Evid Based Complement Alternat Med. (2012) 2012:710750. doi: 10.1155/2012/710750

PubMed Abstract | Crossref Full Text | Google Scholar

179. Wang H, Yang G, Wang S, Zheng X, Zhang W, and Li Y. The most commonly treated acupuncture indications in the United States: A cross-sectional study. Am J Chin Med. (2018) 9:1–33. doi: 10.1142/S0192415X18500738

PubMed Abstract | Crossref Full Text | Google Scholar

180. Liu Q, Ai K, Jiang XR, Yang JJ, Chen L, Cao SH, et al. Research on acupuncture and glial cells: A bibliometric analysis. Medicine. (2024) 103:e38898. doi: 10.1097/MD.0000000000038898

PubMed Abstract | Crossref Full Text | Google Scholar

181. Chen Y, Li D, Li N, Loh P, Guo Y, Hu X, et al. Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain. Front Neurol. (2023) 14:1093849. doi: 10.3389/fneur.2023.1093849

PubMed Abstract | Crossref Full Text | Google Scholar

182. Zeng JC, Chen YX, Li JJ, Wang XD, Xiao X, Zhang RL, et al. Mechanism of analgesic effect of fire needle on peripheral sensitization in rats with neuropathic pain induced by chemotherapy. Acupuncture Res. (2023) 48:1095–102. doi: 10.13702/j.1000-0607.20221165

PubMed Abstract | Crossref Full Text | Google Scholar

183. Long M, Wang Z, Shao L, Bi J, Chen Z, and Yin N. Electroacupuncture pretreatment attenuates cerebral ischemia-reperfusion injury in rats through transient receptor potential vanilloid 1-mediated anti-apoptosis via inhibiting NF-κB signaling pathway. Neuroscience. (2022) 482:100–15. doi: 10.1016/j.neuroscience.2021.12.017

PubMed Abstract | Crossref Full Text | Google Scholar

184. Liao HY, Lin MC, and Lin YW. Acupuncture points injection mitigates chronic pain through transient receptor potential V1 in mice. Iran J Basic Med Sci. (2022) 25:451–9. doi: 10.22038/IJBMS.2022.60121.13327

PubMed Abstract | Crossref Full Text | Google Scholar

185. Inprasit C and Lin YW. TRPV1 responses in the cerebellum lobules V, VIa and VII using electroacupuncture treatment for inflammatory hyperalgesia in murine model. Int J Mol Sci. (2020) 21:3312. doi: 10.3390/ijms21093312

PubMed Abstract | Crossref Full Text | Google Scholar

186. Bhsiao IH, Yen CM, Hsu HC, Liao HY, and Lin YW. Chemogenetics modulation of electroacupuncture analgesia in mice spared nerve injury-induced neuropathic pain through TRPV1 signaling pathway. Int J Mol Sci. (2024) 25:1771. doi: 10.3390/ijms25031771

PubMed Abstract | Crossref Full Text | Google Scholar

187. Hsiao IH and Lin YW. Electroacupuncture reduces fibromyalgia pain by attenuating the HMGB1, S100B, and TRPV1 signalling pathways in the mouse brain. Evid Based Complement Alternat Med. (2022) 2022:2242074. doi: 10.1155/2022/2242074

PubMed Abstract | Crossref Full Text | Google Scholar

188. Liao HY and Lin YW. Electroacupuncture reduces cold stress-induced pain through microglial inactivation and transient receptor potential V1 in mice. Chin Med. (2021) 16:43. doi: 10.1186/s13020-021-00451-0

PubMed Abstract | Crossref Full Text | Google Scholar

189. Yeh YA, Liao HY, Hsiao IH, Hsu HC, and Lin YW. Electroacupuncture reduced fibromyalgia-pain-like behavior through inactivating transient receptor potential V1 and interleukin-17 in intermittent cold stress mice model. Brain Sci. (2024) 14:869. doi: 10.3390/brainsci14090869

PubMed Abstract | Crossref Full Text | Google Scholar

190. Kao FC, Yen CM, Lin MC, Liao HY, Hsu HC, and Lin YW. Acupoint catgut embedding attenuates fibromyalgia pain through attenuation of TRPV1 signaling pathway in mouse. Iran J Basic Med Sci. (2024) 27:66–73. doi: 10.22038/IJBMS.2023.71431.15534

PubMed Abstract | Crossref Full Text | Google Scholar

191. Lai PC, Yen CM, Hsiao IH, Chen YH, and Lin YW. Acupoint catgut embedding diminishes fibromyalgia pain through TRPV1 in the mouse brain. J Integr Neurosci. (2023) 22:97. doi: 10.31083/j.jin2204097

PubMed Abstract | Crossref Full Text | Google Scholar

192. Liao HY and Lin YW. Electroacupuncture attenuates chronic inflammatory pain and depression comorbidity through transient receptor potential V1 in the brain. Am J Chin Med. (2021) 49:1417–35. doi: 10.1142/S0192415X2150066X

PubMed Abstract | Crossref Full Text | Google Scholar

193. Lottering B and Lin YW. Functional characterization of nociceptive mechanisms involved in fibromyalgia and electroacupuncture. Brain Res. (2021) 1755:147260. doi: 10.1016/j.brainres.2020.147260

PubMed Abstract | Crossref Full Text | Google Scholar

194. Yen CM, Wu TC, Hsieh CL, Huang YW, and Lin YW. Distal Electroacupuncture at the LI4 Acupoint Reduces CFA-Induced Inflammatory Pain via the Brain TRPV1 Signaling Pathway. Int J Mol Sci. (2019) 20:4471. doi: 10.3390/ijms20184471

PubMed Abstract | Crossref Full Text | Google Scholar

195. Lin HC, Hsu HC, Liao HY, Chen ALP, and Lin YW. Electroacupuncture modulates programmed cell death 1 ligand 1 on peripheral and central nervous systems in a mouse fibromyalgia pain model. Biomedicines. (2025) 13:396. doi: 10.3390/biomedicines13020396

PubMed Abstract | Crossref Full Text | Google Scholar

196. Lottering B and Lin YW. TRPV1 responses in the cerebellum lobules VI, VII, VIII using electroacupuncture treatment for chronic pain and depression comorbidity in a murine model. Int J Mol Sci. (2021) 22:5028. doi: 10.3390/ijms22095028

PubMed Abstract | Crossref Full Text | Google Scholar

197. Lin HC, Park HJ, Liao HY, Chuang KT, and Lin YW. Accurate chemogenetics determines electroacupuncture analgesia through increased CB1 to suppress the TRPV1 pathway in a mouse model of fibromyalgia. Life (Basel). (2025) 15:819. doi: 10.3390/life15050819

PubMed Abstract | Crossref Full Text | Google Scholar

198. Long M, Wang Z, Zheng D, Chen J, Tao W, Wang L, et al. Electroacupuncture pretreatment elicits neuroprotection against cerebral ischemia-reperfusion injury in rats associated with transient receptor potential vanilloid 1-mediated anti-oxidant stress and anti-inflammation. Inflammation. (2019) 42:1777–87. doi: 10.1007/s10753-019-01040-y

PubMed Abstract | Crossref Full Text | Google Scholar

199. Lin YW and Hsieh CL. Electroacupuncture at Baihui acupoint (GV20) reverses behavior deficit and long-term potentiation through N-methyl-d-aspartate and transient receptor potential vanilloid subtype 1 receptors in middle cerebral artery occlusion rats. J Integr Neurosci. (2010) 9:269–82. doi: 10.1142/s0219635210002433

PubMed Abstract | Crossref Full Text | Google Scholar

200. Yen CM, Hsieh CL, and Lin YW. Electroacupuncture reduces chronic fibromyalgia pain through attenuation of transient receptor potential vanilloid 1 signaling pathway in mouse brains. Iran J Basic Med Sci. (2020) 23:894–900. doi: 10.22038/ijbms.2020.39708.9408

PubMed Abstract | Crossref Full Text | Google Scholar

201. Hsiao IH, Lin MC, Hsu HC, Chae Y, Lin IY, and Lin YW. Electroacupuncture relieves fibromyalgia pain in a female mouse model by augmenting cannabinoid receptor 1 Expression and suppressing astrocyte and microglial activation in nociceptive pathways. Biomedicines. (2025) 13:2112. doi: 10.3390/biomedicines13092112

PubMed Abstract | Crossref Full Text | Google Scholar

202. Hsu HC, Hsieh CL, Lee KT, and Lin YW. Electroacupuncture reduces fibromyalgia pain by downregulating the TRPV1-pERK signalling pathway in the mouse brain. Acupunct Med. (2020) 38:101–8. doi: 10.1136/acupmed-2017-011395

PubMed Abstract | Crossref Full Text | Google Scholar

203. Anh DTN and Lin YW. Electroacupuncture mitigates TRPV1 overexpression in the central nervous system associated with fibromyalgia in mice. Life (Basel). (2024) 14:1605. doi: 10.3390/life14121605

PubMed Abstract | Crossref Full Text | Google Scholar

204. Vickers A and Zollman C. ABC of complementary medicine. Acupuncture. BMJ. (1999) 319:973–6. doi: 10.1136/bmj.319.7215.973

PubMed Abstract | Crossref Full Text | Google Scholar

205. Wu XD, Huang LX, and Zhao JS. Interpretation of China national standard nomenclature and location of meridian points. Zhongguo zhen jiu. (2022) 42:579–82. doi: 10.13703/j.0255-2930.20220117-k0001

PubMed Abstract | Crossref Full Text | Google Scholar

206. Huo J, Zhao J, Yuan Y, and Wang J. Research status of the effect mechanism on catgut-point embedding therapy. Zhongguo zhen jiu. (2017) 37:1251–4. doi: 10.13703/j.0255-2930.2017.11.031

PubMed Abstract | Crossref Full Text | Google Scholar

207. Feng C, Qu Y, Wu J, Chen T, Liu T, Lu J, et al. The efficacy of acupuncture-based chinese medicine in chronic fatigue syndrome: A meta-analysis. Medicine. (2025) 104:e42111. doi: 10.1097/MD.0000000000042111

PubMed Abstract | Crossref Full Text | Google Scholar

208. Zhu J, Ge X, Cao Y, Xiao R, and Deng X. Neuroprotective effects of electroacupuncture in ischemic stroke: from mechanisms to clinical implications. Front Aging Neurosci. (2025) 17:1562925. doi: 10.3389/fnagi.2025.1562925

PubMed Abstract | Crossref Full Text | Google Scholar

209. Hao SJ, Wang S, Bai Y, Lü PZ, Li CX, Zhu LY, et al. Research progress of acupuncture for modulating the inflammatory response in treatment of Parkinson’s disease. Zhen ci yan jiu. (2025) 50:334–40. doi: 10.13702/j.1000-0607.20231039

PubMed Abstract | Crossref Full Text | Google Scholar

210. Liu C, Su Y, Yau YM, Lin H, Chen Y, Fang W, et al. Effect of acupuncture on cognitive impairment induced by sleep deprivation in animal models: a preclinical systematic review and meta-analysis. Front Aging Neurosci. (2025) 17:1560032. doi: 10.3389/fnagi.2025.1560032

PubMed Abstract | Crossref Full Text | Google Scholar

211. Ma J, Yin X, Cui K, Wang J, Li W, and Xu S. Mechanisms of acupuncture in treating depression: a review. Chin Med. (2025) 20:29. doi: 10.1186/s13020-025-01080-7

PubMed Abstract | Crossref Full Text | Google Scholar

212. Xin Y, Zhou S, Chu T, Zhou Y, and Xu A. Protective role of electroacupuncture against cognitive impairment in neurological diseases. Curr Neuropharmacol. (2025) 23:145–71. doi: 10.2174/1570159X22999240209102116

PubMed Abstract | Crossref Full Text | Google Scholar

213. Chen Z, Wang X, Du S, Liu Q, Xu Z, Guo Y, et al. A review on traditional Chinese medicine natural products and acupuncture intervention for Alzheimer’s disease based on the neuroinflammatory. Chin Med. (2024) 19:35. doi: 10.1186/s13020-024-00900-6

PubMed Abstract | Crossref Full Text | Google Scholar

214. Zhang Y and Wang C. Acupuncture and chronic musculoskeletal pain. Curr Rheumatol Rep. (2020) 22:80. doi: 10.1007/s11926-020-00954-z

PubMed Abstract | Crossref Full Text | Google Scholar

215. Wu Z, Liu C, Chan V, Wu X, Huang F, Guo Z, et al. Efficacy of acupuncture in ameliorating anxiety in Parkinson’s disease: a systematic review and meta-analysis with trial sequential analysis. Front Aging Neurosci. (2024) 16:1462851. doi: 10.3389/fnagi.2024.1462851

PubMed Abstract | Crossref Full Text | Google Scholar

216. Li P, Zhao J, Wei X, Luo L, Chu Y, Zhang T, et al. Acupuncture may play a key role in anti-depression through various mechanisms in depression. Chin Med. (2024) 19:135. doi: 10.1186/s13020-024-00990-2

PubMed Abstract | Crossref Full Text | Google Scholar

217. Wang R and Xu JF. Development of research on mechanisms of acupuncture intervention on ischemic stroke and its relationship with microglia. Zhen ci yan ji. (2024) 49:1319–24. doi: 10.13702/j.1000-0607.20230774

PubMed Abstract | Crossref Full Text | Google Scholar

218. Wei TH and Hsieh CL. Effect of acupuncture on the p38 signaling pathway in several nervous system diseases: A systematic review. Int J Mol Sci. (2020) 21:4693. doi: 10.3390/ijms21134693

PubMed Abstract | Crossref Full Text | Google Scholar

219. Zhao JY, Yuan GM, Li PY, Xu Y, Guo YM, and Gong YN. Research progress of acupuncture in attenuating depression via regulating hippocampal neuroplasticity. Zhen ci yan jiu. (2025) 50:439–47. doi: 10.13702/j.1000-0607.20231134

PubMed Abstract | Crossref Full Text | Google Scholar

220. Ren DL, Wei YT, Su ML, Zhu TT, and Yan XK. Progress of researches on the mechanism of acupuncture treatment for Alzheimer’s disease by modulating synaptic plasticity. Zhen ci yan jiu. (2024) 49:858–66. doi: 10.13702/j.1000-0607.20230279

PubMed Abstract | Crossref Full Text | Google Scholar

221. Kang SY, Bang SK, Seo SY, Cho SJ, Choi KH, Han S, et al. Mechanical acupuncture at ST36 attenuates inflammatory pain involving TRPV1 signaling in mice. Int J Mol Sci. (2025) 26:8534. doi: 10.3390/ijms26178534

PubMed Abstract | Crossref Full Text | Google Scholar

222. Li Y, Yin C, Li X, Liu B, Wang J, Zheng X, et al. Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. Int J Mol Sci. (2019) 20:5917. doi: 10.3390/ijms20235917

PubMed Abstract | Crossref Full Text | Google Scholar

223. Ma YQ, Hu QQ, Kang YR, Ma LQ, Qu SY, Wang HZ, et al. Electroacupuncture alleviates diabetic neuropathic pain and downregulates p-PKC and TRPV1 in dorsal root ganglions and spinal cord dorsal horn. Evid Based Complement Alternat Med. (2023) 2023:3333563. doi: 10.1155/2023/3333563

PubMed Abstract | Crossref Full Text | Google Scholar

224. Yang J, Hsieh CL, and Lin YW. Role of transient receptor potential vanilloid 1 in electroacupuncture analgesia on chronic inflammatory pain in mice. BioMed Res Int. (2017) 2017:5068347. doi: 10.1155/2017/5068347

PubMed Abstract | Crossref Full Text | Google Scholar

225. Zhang RY, Zhu BF, Zhao JG, Zhao L, and Wang LK. Electroacupuncture stimulation alleviates inflammatory pain in male rats by suppressing oxidative stress. Physiol Res. (2023) 72:657–67. doi: 10.33549/physiolres.934965

PubMed Abstract | Crossref Full Text | Google Scholar

226. Fang J, Wang S, Zhou J, Shao X, Sun H, Liang Y, et al. Electroacupuncture regulates pain transition through inhibiting PKCϵ and TRPV1 expression in dorsal root ganglion. Front Neurosci. (2021) 15:685715. doi: 10.3389/fnins.2021.685715

PubMed Abstract | Crossref Full Text | Google Scholar

227. Hwang JH, Kang SY, Kang AN, Jung HW, Jung C, Jeong JH, et al. MOK, a pharmacopuncture medicine, regulates thyroid dysfunction in L-thyroxin-induced hyperthyroidism in rats through the regulation of oxidation and the TRPV1 ion channel. BMC Complement Altern Med. (2017) 17:535. doi: 10.1186/s12906-017-2036-1

PubMed Abstract | Crossref Full Text | Google Scholar

228. Ding N, Wu X, Zhao N, Mu D, and Hu J. Current status and reflections on the development of acupuncture-moxibustion technical specification in China. Zhongguo Zhen Jiu. (2025) 45:535–40. doi: 10.13703/j.0255-2930.20241022-k0002

PubMed Abstract | Crossref Full Text | Google Scholar

229. Gao JH, Jiang TY, Jing XH, and Yu XC. Technological innovation and future development of quantitative research on acupuncture manipulation techniques. Zhen Ci Yan Jiu. (2025) 50:531–7. doi: 10.13702/j.1000-0607.20250319

PubMed Abstract | Crossref Full Text | Google Scholar

230. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. (2002) 195:781–8. doi: 10.1084/jem.20011714

PubMed Abstract | Crossref Full Text | Google Scholar

231. Wang C, Lu J, Sha X, Qiu Y, Chen H, and Yu Z. TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia. Exp Mol Med. (2023) 55:347–63. doi: 10.1038/s12276-023-00935-z

PubMed Abstract | Crossref Full Text | Google Scholar

232. Lu J, Wang C, Cheng X, Wang R, Yan X, He P, et al. A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson’s disease. J Neuroinflammation. (2022) 19:113. doi: 10.1186/s12974-022-02484-0

PubMed Abstract | Crossref Full Text | Google Scholar

233. Yuan J, Liu H, Zhang H, Wang T, Zheng Q, and Li Z. Controlled activation of TRPV1 channels on microglia to boost their autophagy for clearance of alpha-synuclein and enhance therapy of parkinson’s disease. Adv Mater. (2022) 34:e2108435. doi: 10.1002/adma.202108435

PubMed Abstract | Crossref Full Text | Google Scholar

234. Lu J, Wu K, Sha X, Lin J, Chen H, and Yu Z. TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer’s disease. Transl Neurodegener. (2024) 13:52. doi: 10.1186/s40035-024-00445-6

PubMed Abstract | Crossref Full Text | Google Scholar

235. Sun JX, Zhu KY, Wang YM, Wang DJ, Zhang MZ, Sarlus H, et al. Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function. A Acta Pharmacol Sin. (2023) 44:766–79. doi: 10.1038/s41401-022-01000-7

PubMed Abstract | Crossref Full Text | Google Scholar

236. Wang SY, Li MM, Wu JT, Sun Y, Pan J, Guan W, et al. Lignans of Schisandra chinensis (Turcz.) Baill inhibits Parkinson’s disease progression through mediated neuroinflammation-TRPV1 expression in microglia. Phytomedicine. (2024) 135:156146. doi: 10.1016/j.phymed.2024.156146

PubMed Abstract | Crossref Full Text | Google Scholar

237. Lu J, Zhou W, Dou F, Wang C, and Yu Z. TRPV1 sustains microglial metabolic reprogramming in Alzheimer’s disease. EMBO Rep. (2021) 22:e52013. doi: 10.15252/embr.202052013

PubMed Abstract | Crossref Full Text | Google Scholar

238. Wang C, Huang W, Lu J, Chen H, and Yu Z. TRPV1-mediated microglial autophagy attenuates alzheimer’s disease-associated pathology and cognitive decline. Front Pharmacol. (2022) 12:763866. doi: 10.3389/fphar.2021.763866

PubMed Abstract | Crossref Full Text | Google Scholar

239. Sha X, Lin J, Wu K, Lu J, and Yu Z. The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease. Cell Death Dis. (2025) 16:14. doi: 10.1038/s41419-024-07328-8

PubMed Abstract | Crossref Full Text | Google Scholar

240. Bok E, Chung YC, Kim KS, Baik HH, Shin WH, and Jin BK. Modulation of M1/M2 polarization by capsaicin contributes to the survival of dopaminergic neurons in the lipopolysaccharide-lesioned substantia nigra in vivo. Exp Mol Med. (2018) 50:1–14. doi: 10.1038/s12276-018-0111-4

PubMed Abstract | Crossref Full Text | Google Scholar

241. Zhang T, Tian Y, Zheng X, Li R, Hu L, Shui X, et al. Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement. CNS Neurosci Ther. (2024) 30:e14432. doi: 10.1111/cns.14432

PubMed Abstract | Crossref Full Text | Google Scholar

242. Li YY, Qin ZH, and Sheng R. The multiple roles of autophagy in neural function and diseases. Neurosci Bull. (2024) 40:363–82. doi: 10.1007/s12264-023-01120-y

PubMed Abstract | Crossref Full Text | Google Scholar

243. He J, He M, Sun M, Chen H, Dou Z, Nie R, et al. The mechanism of acupuncture regulating autophagy: progress and prospect. Biomolecules. (2025) 15:263. doi: 10.3390/biom15020263

PubMed Abstract | Crossref Full Text | Google Scholar