Extrinsic dsDNA, from pathogens such as viruses, bacteria, and parasites, can be internalized into the cytosol in several ways to activate the cGAS-STING pathway (Diamond et al., 2018). The patrol nuclease degrades the dsDNA entering the cell in the lysosome or cytoplasm. In cells with abundant dsDNA or a lack of nuclease, internalized DNA may remain in the cytoplasm and be converted into cGAMP to activate STING (Ablasser et al., 2013). Currently, the evidence indicates that SARS-CoV-2, the etiologic agent of COVID-19, can damage and alter the nervous system, causing headaches and myalgia (Abboud et al., 2020). Another report has suggested that the pain may be related to the increase of type 1 interferons, which is the downstream of STING in young patients (Papa et al., 2021). Simultaneously, an animal experiment has also proved that viral infection induces pain by directly affecting nociceptors in dorsal root ganglion with type 1 interferons (Barragán-Iglesias et al., 2020). The above studies suggest that extrinsic dsDNA-like viruses and bacteria may cause pain via activating the cGAS-STING pathway.

Furthermore, extrinsic dsDNA and intrinsic dsDNA can activate cGAS-STING pathway and induce chronic pain. For example, self-dsDNA was increased and mediated the activation of cGAS-STING pathway in the spinal cord, contributing to the spared nerve injury (SNI)-induced neuropathic pain (Sun et al., 2021). The intrinsic self-dsDNA is composed of nDNA and mtDNA, which can be segregated inaccurately and released into the cytosol, triggering the STING pathway (Bhattacharya et al., 2017). Additionally, in the peripheral neuropathy pain model, DNA damage and the nuclear DNA released are associated with pain production (Canta et al., 2015), suggesting that STING may be activated in that pain model. Another intrinsic dsDNA was mtDNA, which is a component of mitochondria that belongs to the only non-nuclear genome. Compared with nDNA, mtDNA is more unstable and vulnerable to the effects of oxidative stress due to its proximity to mitochondrial reactive oxygen species (mtROS) and a lack of repair machinery. mtDNA stress may contribute to the cGAS-STING pathway activation and type 1 interferon responses in various pathological states, including infectious diseases, cancer, neurodegeneration, and other mitochondria-related illnesses (Zhou et al., 2021). Importantly, it has been established that mtDNA depletion inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3 (Zhou et al., 2021).

Additionally, mitochondrial dysfunction contributes to the etiology of pain, as indicated by microscopic analysis performed on peripheral nerve sensory axons: abundant vacuolated and swollen mitochondria were observed in the rats treated with paclitaxel to induce pain (Canta et al., 2015; Dai et al., 2020). The increase of mtDNA is associated with pain-like behavior (Trecarichi et al., 2022). Additionally, it has evidenced that mtDNA released and activated the cGAS-STING pathway in low back pain model (Ning et al., 2020). Altogether, this evidence above suggests that mtDNA or nuclear DNA released may activate the cGAS-STING pathway in the process of chronic pain.

Several lines of evidence have shown that Toll-like receptors (TLRs) signaling enables the cGAS-STING pathway to induce a strong type 1 interferon response during HIV-1 infection (Siddiqui and Yamashita, 2021). Additionally, TLR4 has been considered essential for activating the cGAS-STING pathway in macrophages stimulated by LPS (Ning et al., 2020), although current studies have suggested that after nerve injury, TLRs are involved in Wallerian degeneration and the generation of neuropathic pain (Thakur et al., 2017). Particularly, TLR3 promotes neuropathic pain by regulating autophagy in rats with L5 spinal nerve ligation model (Chen and Lu, 2017), and knockdown of TLR3 in bone malignancy pain model mice can impair pain thoroughly (Zhang et al., 2020). Furthermore, TLR3 has also been proven to trigger type 1 interferon responses via Toll/IL-1 receptor domain containing adaptor inducing IFN-β (TRIF) signaling to regulate pain and itch (Szöllosi et al., 2019). It is suggested that TLRs may be involved in activating the cGAS-STING pathway in chronic pain, although it remains to be examined.

The cGAS-STING pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type 1 interferon responses (Domizio et al., 2022). Furthermore, the latest research on COVID-19 has revealed that type 1 interferon response, which is activated by cGAS-STING pathway, induces microangiopathic changes and produces neuropathic pain in young patients (Papa et al., 2021). Simultaneously, according to a study of hepatitis C virus patients, IFN-α therapy causes significant somatic pain and promotes major depressive disorder as early as the second week of treatment (Lin et al., 2020), although early reports have demonstrated that IFN-α and IFN-β, two major family members of type 1 interferons, exert an antinociceptive action (Menzies et al., 1992). In addition, STING regulates the type 1 interferon signaling in dorsal root ganglion sensory neurons, which has been disclosed to control nociception in bone cancer pain models (Donnelly et al., 2021). Consistently, in chronic constriction injury-induced neuropathic pain, protein tyrosine phosphatase receptor type D (PTPRD) activates STING-type 1 interferon pathway in dorsal root ganglion and displays an analgesic effect (Sun et al., 2022). In the light of this, researchers have reviewed that IFN-α and IFN-β may rapidly suppress neuronal activity and synaptic transmission to potent analgesia via nongenomic regulation (Tan et al., 2021), while the discrepancy in antinociceptive against pronociceptive effects of type 1 interferons may ascribe to various conditions, and the exact role of STING/type 1 interferons in chronic pain requires further investigation.

STING predominantly inhabits the endoplasmic reticulum to regulate innate immune signaling processes and recruits NLRP3 to the ER to promote the inflammasome formation in the HSV-1 infection (Wang et al., 2020). Lipopolysaccharide (LPS) activates STING and afterward upregulates NLRP3 expression in acute lung injury (Ning et al., 2020). Simultaneously, an increasing body of evidence verified that NLRP3 inflammasome controls the processing of proinflammatory cytokine interleukin 1β (IL-1β) and is implicated in chronic pain (Pan et al., 2018; Chen et al., 2021). In another study of lower back pain, NLRP3 activation in nucleus pulposus cells was associated with cGAS and STING and participated in chronic pain (Tian et al., 2020). The inhibitor of NLRP3 inflammasome can effectively modify nitroglycerin-induced mechanical hyperalgesia (He et al., 2019). Therefore, NLRP3 has become an emerging therapeutic target for chronic pain, and it shows promise that STING may regulate NLRP3 to participate in chronic pain.

Nuclear factor-kappa B (NF-κB) is an important nuclear transcription factor in almost all cell types and participates in numerous biological processes, including inflammation, cell differentiation, immunity, cell growth and apoptosis, and tumorigenesis (Ghosh and Dass, 2016). STING activation can trigger nuclear factor κB (NF-κB) signaling to mediate immune defense against tumors and viral infections (Yum et al., 2021). Simultaneously, STING antagonist H-151 has been shown that suppresses STING/NF-κB-mediated inflammation to ameliorate psoriasis (Pan et al., 2021). Notably, the latest research in neuropathic pain has indicated that STING may activate the NF-κB and release the proinflammatory cytokines IL-6 in the spinal cord to aggravate chronic pain. However, injecting STING antagonist C-176 can provide an analgesic effect and reverse the increased expression of NF-κB (Sun et al., 2021). Additionally, NF-κB is a transcription factor for various cytokines, including CX3CL1, IL-1β, IL-6, and TNF-α, to induce peripheral and central sensitization in chronic pain (Sun et al., 2012; Liu et al., 2018; Xiang et al., 2019; Li Y. et al., 2020; Xu et al., 2021). Undoubtedly, NF-κB activation may contribute to chronic pain; therefore, as an important mediator of NF-κB, STING is supposed to play a significant role in chronic pain.

Evidence accumulates that STING pathway is involved in inflammation (Chin, 2019); for instance, STING-mediated type 1 interferons regulates the elevation of proinflammatory cytokine profile with increased TNF-α, IL-6, and IL-1β in microglia of traumatic brain injury (Abdullah et al., 2018). Moreover, these studies have revealed that the cGAS-STING pathway was activated, and the inflammatory cytokines IL-6 and CXCL10 were released in mitochondrial dysfunction (Zhou et al., 2021). Additionally, in cerebral ischemic stroke, cGAS knockdown promotes microglial M2 polarization to alleviate inflammation (Jiang et al., 2021). Emerging evidence suggested that inflammation plays an essential role in chronic pain (Ji et al., 2016, 2018): The upregulation of inflammatory mediators (TNF-α, IL-6, and IL-1β) in the spinal cord has been evidenced that might be involved in the process of bone cancer pain. Inhibition of endoplasmic reticulum stress may decrease the inflammatory mediators and show an antinociception effect (Wei et al., 2016; Mao et al., 2020). Particularly, in inflammatory pain, magnetic resonance imaging (MRI) and histopathology have demonstrated that inflammation caused by cGAS, STING, and NLRP3 is associated with intervertebral disc degeneration in low back pain (Zhang et al., 2022). Moreover, STING can also participate in the inflammatory reaction process of neuropathic pain. In spinal cord injury mice, STING knockout may alleviate inflammatory response (Wang et al., 2019); in spared nerve injury rats, STING inhibitor C-176 administration provides an antinociceptive effect that is reversed by injecting recombinant IL-6 (Sun et al., 2021), which indicates that STING is an essential downstream factor for chronic pain by regulating IL-6 expression. Accordingly, it would not surprise that activation of the cGAS-STING pathway may induce inflammation to mediate inflammatory and neuropathic pain.

The cGAS-STING pathway has a significant role in the immune, and emerging studies provide solid evidence that cGAS-STING is mainly attributed to antigen-presenting cell (APC)-mediated activation of CD8⁺ T cells (Flood et al., 2019) and spontaneous CD8⁺ T cell priming against tumors was defective in mice lacking STING (Woo et al., 2014). Meanwhile, cGAS-STING-mediated DNA sensing has been reported that maintains CD8⁺ T cell stemness and promotes anti-tumor T cell therapy (Li W. et al., 2020). Although the clinical research disclosed that STING agonist ADU-S100 might induce CD8⁺ T cell immune response at a low dose, when administered at a high dose, the CD8⁺ T cell death, and compromised anti-tumor immunity (Sivick et al., 2018), it is no doubt that STING mediates CD8⁺ T cells.

A variety of inflammatory pain processes are believed to be mediated by T cells, including rheumatoid arthritis, intestinal inflammation, etc. (Basso et al., 2015; Swain et al., 2022). Recent studies have found that T cells are also involved in neuropathic pain: CD8⁺ T cells and endogenous IL-10 are required to resolve chemotherapy-induced neuropathic pain (Krukowski et al., 2016); educating CD8⁺ T cells can prevent and resolve chemotherapy-induced peripheral neuropathy in mice (Laumet et al., 2019; Singh et al., 2022). Intriguingly, in the bone cancer pain model which may involve both inflammatory pain and neuropathic pain, systemic administration of STING activator DMXAA attenuated the measures of spontaneous and ongoing pain; the analgesic effect may attribute to the increasing proportion of CD8⁺ T cells in the bone marrow tumor microenvironment (Donnelly et al., 2021). Therefore, these findings suggest that the cGAS-STING pathway may involve chronic pain by mediating the immunity of CD8⁺ T cells.

Autophagy is a lysosomal degradation pathway that maintains tissue homeostasis by recycling damaged and aged cellular components, which plays a significant role in developing the nervous system, neuronal function, and survival (Liu X. et al., 2019). Emerging studies showed that innate immunity-related proteins control the progress of autophagy (Wild et al., 2011). Extracellular M. tuberculosis DNA induces autophagy by activating the cGAS-STING pathway, suggesting a link between STING and autophagy (Watson et al., 2012). Additionally, injecting the activator of IRF3, the downstream protein of the cGAS-STING pathway, can inhibit the fusion of the autophagosome with the lysosome to reduce autophagy flux (67), indicating that the activation of the STING pathway may impair the autophagy. In neuropathic pain, autophagy flux is impaired and mainly exists in astrocytes during the maintenance of the study by Li et al. (2021) and Liao et al. (2022); no matter the stage of neuropathic pain induction or maintenance, upregulation of autophagy can suppresses pain behavior (Li et al., 2021). Researchers suggest that upregulated autophagic activities may facilitate myelin clearance, promote nerve regeneration, and reduce pain. Furthermore, the cGAS-STING pathway has been reported to directly interact with microtubule-associated protein light chain 3 (LC3) and subsequent autophagy to regulate the innate immune responses (Liu D. et al., 2019). The expression of LC3 is upregulated in GABAergic interneurons of rat spinal dorsal horn after SNL, suggesting that autophagic disruption following SNL might be involved in the induction and maintenance of neuropathic pain (Liu X. et al., 2019). Intrathecal injection of autophagy activator exerts an analgesic effect on neuropathic pain by activating LC3 in astrocytes (Yuan and Fei, 2021). It can be suggested that STING may interact with LC3 to aggravate chronic pain further. The role of autophagy in inflammatory pain has been studied relatively less, while a study by Liu found that CFA-induced inflammatory pain can be alleviated by restoring autophagic flux in the spinal cord (Liu et al., 2022). Autophagy may mediate both inflammatory and neuropathic pain, although there is no solid evidence to confirm this hypothesis, it is still appropriate to predict that STING may mediate autophagy flux and contribute to chronic pain.

Apoptosis is a form of programmed cell death and shrinkage when cells encounter stress or damage (Liao et al., 2022). There is evidence for this occurring that STING-dependent apoptosis directly through the interaction of IRF3 and BCL2-associated x, apoptosis regulator (Bax) (Sze et al., 2013), and in microglia and other immune cells, HSV-1 at a high viral load can trigger cGAS/STING-dependent apoptosis (Reinert et al., 2021). Additionally, STING-IRF3 contributes to lipopolysaccharide-induced cardiac apoptosis via activating NLRP3 (Li et al., 2019). Consequently, cGAS-STING pathway is essential for apoptosis regulation. Furthermore, apoptotic activity in the injured nerve, dorsal root ganglia, and spinal cord has changed during neuropathic pain formation (Liao et al., 2022). The number of cleaved caspase-3 in the spinal cord increased on days 8 and 14 after nerve injury (Fu et al., 2017). Meanwhile, increased spinal cell apoptosis may probably induce inflammatory pain (Baniasadi et al., 2020). Although there is no clear evidence demonstrating that inhibiting apoptotic activities could attenuate pain behavior, daily hyperbaric oxygen therapy has been proved to suppress pain behavior and reduce apoptotic activities of GABAergic neurons in the spinal dorsal horn of rats (Fu et al., 2017). The apoptosis level was increased in osteoarthritic, which develops slowly and worsens over time, accompanied by chronic pain (Aigner et al., 2001); recently, it has been evidenced that STING might induce apoptosis and senescence in chondrocytes via NF-κB pathway in osteoarthritic mice; STING knockdown may reduce the level of chondrocyte apoptosis and ameliorate the symptom (Guo et al., 2021). Simultaneously, epigallocatechin gallate also has been found that reduces the apoptotic rate via inhibiting the cGAS-STING pathway activation in nucleus pulposus cells of low back pain models (Tian et al., 2020). The process of apoptosis may contribute to the pathology of inflammatory or neuropathic pain. In view of cGAS-STING that can promote apoptosis in various diseases, it is proposed that cGAS-STING may induce apoptosis and promote chronic pain.