• Zhe Li, Shao-Qiu He, Qian Xu, Fei Yang, Vinod Tiwari, Qin Liu, Zongxiang Tang, Liang Han, Yu-Xia Chu, Yun Wang, Niyada Hin, Takashi Tsukamoto, Barbara Slusher, Xiaowei Guan, Feng Wei, Srinivasa N Raja, Xinzhong Dong, and Yun Guan.
• The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Department of Anesthesiology and Critical Care Medicine, 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 Department of Human Anatomy, Nanjing Medical University, Nanjing 210029, China Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
• Pain. 2014 Aug 1; 155 (8): 161316211613-1621.

AbstractMas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist-induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects.Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

29 keywords...

hide…