title: 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: 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.
authors: Shao-Qiu
authors: SQ
authors: He
authors: Zhe
authors: Z
authors: Li
authors: Yu-Xia
authors: YX
authors: Chu
authors: Liang
authors: L
authors: Han
authors: Qian
authors: Q
authors: Xu
authors: Man
authors: M
authors: Li
authors: Fei
authors: F
authors: Yang
authors: Qin
authors: Q
authors: Liu
authors: Zongxiang
authors: Z
authors: Tang
authors: Yun
authors: Y
authors: Wang
authors: Niyada
authors: N
authors: Hin
authors: Takashi
authors: T
authors: Tsukamoto
authors: Barbara
authors: B
authors: Slusher
authors: Vinod
authors: V
authors: Tiwari
authors: Ronen
authors: R
authors: Shechter
authors: Feng
authors: F
authors: Wei
authors: Srinivasa N
authors: SN
authors: Raja
authors: Xinzhong
authors: X
authors: Dong
authors: Yun
authors: Y
authors: Guan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D010446:Peptide Fragments / Q000008:administration & dosage; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency* / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: C000591604:MrgC protein, mouse; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C571042:bovine adrenal medulla 8-22
keywords: Analgesia; Dorsal root ganglion; MrgC; Neuropathic pain