He Shao-Qiu, Li Zhe, Chu Yu-Xia, Han Liang, Xu Qian, Li Man, Yang Fei, Liu Qin, Tang Zongxiang, Wang Yun, Hin Niyada, Tsukamoto Takashi, Slusher Barbara, Tiwari Vinod, Shechter Ronen, Wei Feng, Raja Srinivasa N, Dong Xinzhong, Guan Yun
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, MD 21201, USA Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USA Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
Pain. 2014 Mar;155(3):534-544. doi: 10.1016/j.pain.2013.12.008. Epub 2013 Dec 11.
Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homologue, MrgX1, and is located specifically in small-diameter dorsal root ganglion neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the miniature excitatory postsynaptic currents frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn neurons of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.
慢性神经性疼痛通常对目前的药物治疗无效。啮齿动物的马斯相关G蛋白偶联受体C亚型（MrgC）与其人类同源物MrgX1具有高度同源性，且特异性地位于小直径背根神经节神经元中。然而，关于MrgC在慢性疼痛状态中的作用的证据一直存在差异且不一致。因此，MrgX1作为人类疼痛治疗靶点的治疗价值仍不确定。在此，我们发现鞘内注射BAM8-22（一种15氨基酸肽MrgC激动剂）和JHU58（一种新型二肽MrgC激动剂）可抑制大鼠L5脊髓神经结扎（SNL）后的机械性和热超敏反应。鞘内注射JHU58诱导的疼痛抑制在SNL大鼠中呈剂量依赖性。重要的是，在Mrg簇基因敲除（Mrg KO）小鼠中药物疗效丧失，并且在SNL大鼠中被鞘内MrgC siRNA基因沉默和选择性MrgC受体拮抗剂阻断，这表明药物作用依赖于MrgC。此外，在三叉神经病理性疼痛小鼠模型中，向同侧尾侧亚核微量注射JHU58可抑制野生型小鼠而非Mrg KO小鼠的机械性超敏反应。最后，JHU58减弱了三叉神经损伤后小鼠延髓背角神经元以及SNL后小鼠腰脊髓背角神经元的微小兴奋性突触后电流频率。我们提供了多条证据表明，在脊髓而非外周部位的MrgC激动作用可能构成一种新 的疼痛抑制机制，该机制涉及在不同的啮齿动物神经性疼痛模型中抑制外周兴奋性输入到突触后背角神经元上。
