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 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.

Proton-Sensing GPCRs in Health and Disease

“…Mechanistically, GPR151 seems to interact with the purinergic receptor P2X3 in sensory neurons. As a consequence, the activity of P2X3 increases causing enhanced activity of sensory neurons and subsequent activation of spinal microglia under neuropathic pain conditions [137].…”

Roles of Long Non-coding RNAs in the Development of Chronic Pain

“…In addition, P2X 3 and P2X 7 receptors have been found to be regulated by lncRNAs ( Seino et al, 2006 ; Peng H. et al, 2017 ). The two receptors play a role in the development of chronic pain ( Wu et al, 2021 ; Xia et al, 2021 ). Furthermore, the levels of pro-inflammatory factors, such as IL-1β, IL-6, IL-12, and TNF-α ( Xia et al, 2018 ; Li Z. et al, 2020 ; Pan et al, 2020 ), have been found to change in chronic pain after lncRNA downregulation.…”

“…Western blot analysis results suggested that the Gm14461 knockdown could downregulate the expression of CGRP and P2X 3 / 7 receptors at the protein level in TN mice. The three proteins are reported to participate in the development of neuropathic pain ( Hansen et al, 2016 ; Wu et al, 2021 ; Xia et al, 2021 ). Moreover, Gm14461 upregulates the expression of TNF-α, IL-1β, and IL-6 ( Xu et al, 2020 ).…”

Role of Epigenetic Mechanisms in Chronic Pain

“…CXCR3 is a key player in the pathophysiological process of many inflammatory conditions and associated to pain modulation in DRG and spinal cord [ 67 ]. GPR151 has been associated to DRG hyperexcitability in neuropathic chronic pain [ 68 ]. Methylation changes are not specific to neuropathic pain, as different forms of chronic pain, like chronic inflammatory or visceral, were also accompanied by different methylation states [ 69 , 70 , 71 ].…”