MINI REVIEW article
Front. Mol. Neurosci.
Sec. Pain Mechanisms and Modulators
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1675814
Neurochemical Crossroads: Exploring the Neurotransmitter Network in Chronic Pain and Depression Comorbidity
Provisionally accepted
- 1Department of Anesthesiology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
- 2Department of Anesthesiology, Fudan University Minhang Hospital, Shanghai, China
- 3Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- 4Department of Anesthesiology, Department of Cardiology, Minhang Hospital, Fudan University, Shanghai, China
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Chronic pain and depression often co-occur, exhibiting a complex, bidirectional relationship that significantly exacerbates the clinical burden and complicates treatment strategies. Recent studies have identified neurochemical mechanisms as the fundamental biological basis for this interaction. Specifically, the imbalance between excitatory glutamate and inhibitory γ-aminobutyric acid (GABA), dysfunction of the endogenous opioid system, and dysregulation of various neuropeptides and non-classical neurotransmitters collectively constitute the neurobiological foundation of disturbances in pain perception and emotional regulation. Glutamate-mediated synaptic excitation and the reduction of GABA's inhibitory function contribute to central sensitization and the abnormal processing of negative emotions. The endogenous opioid system plays a critical role in alleviating pain and emotional disturbances by regulating descending pain control pathways and the limbic system, with receptor dysfunction and expression imbalance being key mechanisms in the comorbidity. Additionally, neuropeptides such as substance P, corticotropin-releasing factor (CRF), and oxytocin participate in stress responses, reward modulation, and emotional control, thereby exacerbating the pathological connection between chronic pain and depression. This review collects the most recent findings on neurochemical interactions in the comorbidity of chronic pain and depression. The goal of this summary is to further our understanding of the molecular mechanisms in this comorbidity, as well as provide theoretical support for intervening in the neurotransmitter system in a targeted way.
Keywords: Chronic Pain, Depression, Glutamate, Excitatory-Inhibitory balance, GABA, endogenous opioid system, Neuropeptides, Neurochemical mechanisms
Received: 29 Jul 2025; Accepted: 19 Sep 2025.
Copyright: © 2025 Ma, Zhang, Tao and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhijie Lu, luzhijie@fudan.edu.cn
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