MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain.

Abstract

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.

• Authors: Shao-Qiu He, Zhe Li, Yu-Xia Chu, Liang Han, Qian Xu, Man Li, Fei Yang, Qin Liu, Zongxiang Tang, Yun Wang, Niyada Hin, Takashi Tsukamoto, Barbara Slusher, Vinod Tiwari, Ronen Shechter, Feng Wei, Srinivasa N Raja, Xinzhong Dong, Yun Guan
• Journal: Pain (Pain) Vol. 155 Issue 3 Pg. 534-544 (Mar 2014) ISSN: 1872-6623 [Electronic] United States
• PMID: 24333779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• MrgC protein, mouse
• Peptide Fragments
• Receptors, G-Protein-Coupled
• bovine adrenal medulla 8-22

Topics

• Animals
• Cells, Cultured
• Excitatory Postsynaptic Potentials (drug effects, physiology)
• HEK293 Cells
• Humans
• Injections, Spinal
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neuralgia (drug therapy, genetics, metabolism)
• Pain Measurement (drug effects, methods)
• Peptide Fragments (administration & dosage)
• Presynaptic Terminals (drug effects, metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (agonists, deficiency, genetics)
• Sensory Receptor Cells (drug effects, metabolism)