The Complexity of Neuropathic Pain and Central Sensitization: Exploring Mechanisms and Therapeutic Prospects

Neuropathic pain is a common pain syndrome, which seriously affects the quality of life of patients. The mechanism of neuropathic pain is complex. Peripheral tissue injury can trigger peripheral sensitization; however, what really plays a key role is the sensitization of the central nervous system. Central sensitization is a key factor in the perception of chronic pain. Central sensitization refers to the increased sensitivity of the central nervous system to pain treatment, which is related to the change of the functional connection mode of the neural network. The current study aims to reveal the basic molecular mechanisms of central sensitization, including the involvement of P2 purine X4 receptor and brain-derived neurotrophic factor. In terms of treatment, although there are drugs and physical therapy, the accuracy of targeting is limited and the efficacy needs to be further improved. Future therapeutic strategies may involve the development of new drugs designed to specifically inhibit the central sensitization process. This article focuses on the effector molecules involved in central sensitization, aiming to elucidate the pathogenesis of neuropathic pain and provide a basis for the development of more effective treatment models.

Keywords

neuropathic pain

central sensitization

P2 purine X4 receptor

brain-derived neurotrophic factor

Funding

CY2022-QN-A03/Fund Project of the Second Hospital of Lanzhou University

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Fig. 1.

Peripheral sensitization mechanism map of neuropathic pain. Following peripheral nerve or tissue injury, immune cells (like mast cells and basophils) liberate a range of inflammatory mediators, encompassing interleukin-6 (IL-6), interleukin-1 $\beta{}$ (IL-1 $\beta{}$ ), substance P, tumor necrosis factor- $\alpha{}$ (TNF- $\alpha{}$ ), insulin-like growth factor (IGF), and nerve growth factor (NGF). These inflammatory mediators orchestrate peripheral sensitization via the subsequent mechanisms: (1) Activation of TRPV1: Inflammatory factors stimulate TRPV1 channels in peripheral nerves, inducing an augmentation of calcium (Ca ${}^{2+}$ ) influx and elevated synthesis and release of NGF; (2) Activation of Nav1.8: Inflammatory factors trigger Nav1.8 channel activity in peripheral nerves, resulting in the influx of sodium ions (Na ${}^{+}$ ). The internal Na ${}^{+}$ flow additionally activates the voltage-gated calcium channel, intensifying Ca ${}^{2+}$ flow; (3) NGF-induced signaling pathway: NGF stimulates TrkA receptors on peripheral nerves, initiating PKC and PI3K pathways. TrkA receptor activation amplifies Nav1.8 activity, subsequently fostering sensitization of peripheral receptors; furthermore, inflammatory factors discharged by immune cells can activate their Toll-like receptors (TLR), consequently setting off the MAPK pathway and the NF- $\kappa{}$ B pathway, which further elevates the secretion of inflammatory factors. These cumulative effects result in heightened activity of peripheral afferent pathways, rendering them more receptive to pain stimuli. This subsequently conveys an increased volume of pain information to the central nervous system, thereby establishing a fundamental groundwork for the establishment of central sensitization. PGE2, Prostaglandin E2; COX-2, Cyclooxygenase-2; TRPV1, Transient Receptor Potential Cation Channel Subfamily V Member 1; PKC, Protein Kinase C; PI3K, Phosphoinositide 3-Kinase; TrkA, Tropomyosin Receptor Kinase A; NF- $\kappa{}$ B, Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; MAPK, Mitogen-Activated Protein Kinase.

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J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X