4.7 Article

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

期刊

BRAIN
卷 144, 期 -, 页码 3405-3420

出版社

OXFORD UNIV PRESS
DOI: 10.1093/brain/awab245

关键词

GPR151; P2X3 ion channel; microglia; dorsal root ganglion; neuropathic pain

资金

  1. Zhejiang Provincial Natural Science Foundation of China [LZ18C090002]
  2. National Natural Science Foundation of China [81971050, 31771162]
  3. China Postdoctoral Science Foundation [2019M662024]
  4. MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University

向作者/读者索取更多资源

GPR151 in nociceptive dorsal root ganglion neurons plays a crucial role in the pathogenesis of neuropathic pain by controlling neuronal hyperexcitability and promoting spinal microglial activation, indicating its potential as a therapeutic target for neuropathic pain treatment.
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.

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