The P2X7 Purinergic Receptor Modulates Neuroimmune and Neuronal Signaling in the Pathogenesis of Neuropathic Pain

Summary

This article describes the role of the P2X7 receptor in the participation of astrocytes, neurons, and microglia in neuropathic pain (NPP). Targeting the P2X7 receptor could be a molecular target for NPP therapy.

Abstract

Primary and secondary injuries of the nervous system can induce neuropathic pain (NPP), which severely impacts patients' physical and mental health and imposes a significant economic burden on individuals, families, and society. Currently, effective curative treatments remain elusive. Consequently, investigating the molecular basis of NPP's pathological mechanisms is crucial for developing targeted therapies. The ion channel P2X7 purinergic receptor (P2X7R) is widely expressed in the nervous system and plays a vital role in maintaining its functional stability. Accumulating evidence indicates that P2X7R is a pain-related molecule involved in the initiation and progression of NPP. The activation or upregulation of P2X7R contributes to NPP by mediating the activities of immune cells, glial cells, and neurons, regulating intercellular interactions among them, enhancing sensory signal transmission and synaptic plasticity, and ultimately leading to central sensitization. Notably, targeted inhibition of P2X7R activation using specific antagonists (e.g., A438079, A740003, and BBG) exhibits pharmacological analgesic properties. Furthermore, downregulating P2X7R expression in tissues/cells via alternative approaches (such as pharmacological agents, cell therapy, and physical therapy) also demonstrates therapeutic potential against NPP. This review comprehensively discusses the mechanisms by which P2X7R regulates both neuronal and non-neuronal cells in NPP. Given its characteristics, targeting P2X7R expression or antagonizing its activity represents a promising, novel pharmacological strategy for NPP treatment.

Introduction

Neuropathic pain (NPP), a chronic condition resulting from lesions or diseases of the somatosensory nervous system, severely compromises patients' quality of life. It manifests as spontaneous pain (e.g., burning, tingling), hyperalgesia, and allodynia, in which innocuous stimuli such as light touch provoke pain. In addition, it is worth noting that even after the nociceptive stimulation is eliminated, the pain can still exist, which may be related to the unrepaired nerve injury. Pain induced by nerve injury can spread to adjacent areas, and its potential pathophysiology involves peripheral and central sensitization, which involves many factors, including chan....