GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation

• Published in: Brain (London, England : 1878) England : 1878), 2021-12, Vol.144 (11), p.3405-3420
• Main Authors: Xia, Li-Ping, Luo, Hao, Ma, Qiang, Xie, Ya-Kai, Li, Wei, Hu, Hailan, Xu, Zhen-Zhong
• Format: Article
• Language: English
• Subjects: Animals; Ganglia, Spinal - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Microglia - metabolism; Neuralgia - metabolism; Nociceptors - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Purinergic P2X3 - metabolism
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awab245

Neuropathic pain is a major health problem that affects up to 7-10% of the population worldwide. Currently, neuropathic pain is difficult to treat because of its elusive mechanisms. Here we report that orphan G protein-coupled receptor 151 (GPR151) in nociceptive sensory neurons controls neuropathic pain induced by nerve injury. GPR151 was mainly expressed in non-peptidergic C-fibre dorsal root ganglion neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury-induced neuropathic pain-like behaviour but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for chronic constriction injury-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, GPR151 coupled with P2X3 ion channels and promoted their functional activities in neuropathic pain-like hypersensitivity. Knockout of Gpr151 suppressed P2X3-mediated calcium elevation and spontaneous pain behaviour in chronic constriction injury mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and dorsal root ganglion neuronal excitability. Furthermore, knockdown of P2X3 in dorsal root ganglia reversed chronic constriction injury-induced CSF1 upregulation, spinal microglial activation and neuropathic pain-like behaviour. Finally, the coexpression of GPR151 and P2X3 was confirmed in small-diameter human dorsal root ganglion neurons, indicating the clinical relevance of our findings. Together, our results indicate that GPR151 in nociceptive dorsal root ganglion neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.