Department of Chemistry and Biochemistry, The University of Texas at Austin , Austin, Texas 78712, United States.
School of Behavioral and Brain Sciences, The University of Texas at Dallas , Richardson, Texas 75080, United States.
ACS Chem Neurosci. 2017 Aug 16;8(8):1801-1811. doi: 10.1021/acschemneuro.7b00200. Epub 2017 Jul 13.
Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (σ1R) is known to be a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Conversely, relatively little is known about σ2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of σ1R and σ2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model. In agreement with previous reports, we find that σ1R ligands given intrathecally (IT) produce relief of SNI-induced mechanical hypersensitivity. We also find that the putative σ2R/Tmem97 agonists DKR-1005, DKR-1051, and UKH-1114 (K ∼ 46 nM) lead to relief of SNI-induced mechanical hypersensitivity, peaking at 48 h after dosing when given IT. This effect is blocked by the putative σ2R/Tmem97 antagonist SAS-0132. Systemic administration of UKH-1114 (10 mg/kg) relieves SNI-induced mechanical hypersensitivity for 48 h with a peak magnitude of effect equivalent to 100 mg/kg gabapentin and without producing any motor impairment. Finally, we find that the TMEM97 gene is expressed in mouse and human dorsal root ganglion (DRG) including populations of neurons that are involved in pain; however, the gene is also likely expressed in non-neuronal cells that may contribute to the observed behavioral effects. Our results show robust antineuropathic pain effects of σ1R and σ2R/Tmem97 ligands, demonstrate that σ2R/Tmem97 is a novel neuropathic pain target, and identify UKH-1114 as a lead molecule for further development.
神经病理性疼痛是一个重要的医学问题，目前有效的治疗方法很少。西格玛 1 受体（σ1R）已知是治疗神经病理性疼痛的潜在靶点，该受体的拮抗剂在临床前模型中有效，目前正在进行 II 期临床试验。相反，相对较少的是σ2R，它最近被确定为跨膜蛋白 97（Tmem97）。我们生成了一系列 σ1R 和 σ2R/Tmem97 激动剂和拮抗剂，并在小鼠 spared 神经损伤（SNI）模型中测试了它们的疗效。与以前的报告一致，我们发现鞘内（IT）给予 σ1R 配体可缓解 SNI 引起的机械性超敏反应。我们还发现，假定的 σ2R/Tmem97 激动剂 DKR-1005、DKR-1051 和 UKH-1114（K∼46 nM）可缓解 SNI 引起的机械性超敏反应，在给药后 48 小时达到峰值。这种作用被假定的 σ2R/Tmem97 拮抗剂 SAS-0132 阻断。系统给予 UKH-1114（10 mg/kg）可缓解 SNI 引起的机械性超敏反应 48 小时，其效应峰值与 100 mg/kg 加巴喷丁相当，且不产生任何运动障碍。最后，我们发现 TMEM97 基因在小鼠和人背根神经节（DRG）中表达，包括参与疼痛的神经元群体；然而，该基因也可能在非神经元细胞中表达，这可能导致观察到的行为效应。我们的结果显示 σ1R 和 σ2R/Tmem97 配体具有强大的抗神经病理性疼痛作用，表明 σ2R/Tmem97 是一个新的神经病理性疼痛靶点，并确定 UKH-1114 是进一步开发的先导分子。
