Papers of the Week

Neuropathic pain is a major health problem that affects up to 7-10% of the population worldwide. Currently, neuropathic pain is difficult to treat due to 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 nonpeptidergic C-fiber dorsal root ganglion (DRG) neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury (CCI)-induced neuropathic pain-like behavior but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for CCI-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 behavior in CCI mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and DRG neuronal excitability. Furthermore, knockdown of P2X3 in DRGs reversed CCI-induced CSF1 upregulation, spinal microglial activation, and neuropathic pain-like behavior. Finally, the co-expression of GPR151 and P2X3 was confirmed in small-diameter human DRG neurons, indicating the clinical relevance of our findings. Together, our results suggest that GPR151 in nociceptive DRG neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.