INRAe, UMR 1280, Physiopathologie des Adaptations Nutritionnelles, CHU Hôtel-Dieu, Nantes, France (F.K.-C., M.T., K.O.) and Physiogenex SAS, Prologue Biotech, Rue Pierre et Marie Curie, Laboratoryège-Innopole, France (F.B., T.S.).
INRAe, UMR 1280, Physiopathologie des Adaptations Nutritionnelles, CHU Hôtel-Dieu, Nantes, France (F.K.-C., M.T., K.O.) and Physiogenex SAS, Prologue Biotech, Rue Pierre et Marie Curie, Laboratoryège-Innopole, France (F.B., T.S.)
J Pharmacol Exp Ther. 2020 Nov;375(2):367-375. doi: 10.1124/jpet.120.000105. Epub 2020 Sep 10.
Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that (Epstein-Barr virus-induced gene 2) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells, and the endogenous ligand is the oxysterol 7,25-dihydroxycholesterol (7,25-OHC). The role of GPR183 in the central nervous system is not well characterized, and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7,25-OHC-induced calcium mobilization with IC values below 50 nM. intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand 7,25-OHC in naïve mice induced dose-dependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. SIGNIFICANCE STATEMENT: We have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.
神经病理性疼痛是一种使人衰弱的公共健康问题，急需寻找新的非麻醉性治疗靶点。我们通过对神经损伤后背角脊髓的无偏转录组筛选，发现（Epstein-Barr 病毒诱导基因 2）在大鼠慢性缩窄性损伤（CCI）后上调。GPR183 是一种趋化性受体，其作用是成熟 B 细胞，内源性配体是氧化固醇 7,25-二羟胆固醇（7,25-OHC）。GPR183 在中枢神经系统中的作用尚未得到很好的描述，其在疼痛中的作用尚不清楚。用于 GPR183 的商业探针的特性限制了它们作为药理学工具的使用，无法用于剖析该受体在病理生理环境中的作用。我们使用 模型，筛选了 500 万个化合物库，鉴定出几种新型 GPR183 的小分子拮抗剂，其对 GPR183 的抑制作用具有纳摩尔效力。这些化合物能够拮抗 7,25-OHC 诱导的钙动员，IC 值低于 50 nM。在 CCI 手术后疼痛高峰时鞘内注射这些拮抗剂，逆转了雄性和雌性小鼠的痛觉过敏。在未处理的小鼠中，急性鞘内注射 GPR183 配体 7,25-OHC 可诱导剂量依赖性痛觉过敏。重要的是，这种效应被我们的新型 GPR183 拮抗剂阻断，表明脊髓 GPR183 激活是致痛的。这些研究首次揭示了 GPR183 在神经病理性疼痛中的作用，并确定该受体是治疗干预的潜在靶点。
我们已经鉴定出几种新型 GPR183 拮抗剂，其对 GPR183 的抑制作用具有纳摩尔效力。使用这些拮抗剂，我们证明了脊髓 GPR183 信号传导是致痛的。这些研究首次揭示了 GPR183 在神经病理性疼痛中的作用，并确定该受体是治疗干预的潜在靶点。
