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

Abstract

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.

• Authors: Li-Ping Xia, Hao Luo, Qiang Ma, Ya-Kai Xie, Wei Li, Hailan Hu, Zhen-Zhong Xu
• Journal: Brain : a journal of neurology (Brain) Vol. 144 Issue 11 Pg. 3405-3420 (12 16 2021) ISSN: 1460-2156 [Electronic] England
• PMID: 34244727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Receptors, G-Protein-Coupled
• Receptors, Purinergic P2X3

Topics

• 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)