The treatment of neuropathic pain continues to challenge clinicians, in part because of limited efficacy of available treatments and a lack of pain-specific drug targets. Mas-related G-protein-coupled receptors (Mrgprs) represent a novel family of G-protein-coupled receptors (GPCRs) that are specifically expressed in small-diameter sensory neurons. Our preliminary work suggests that some Mrgprs, in particular MrgprC, may constitute a novel inhibitory system for persistent pain. Intrathecal administration of a peptide (BAM 8-22) and a small molecule non-peptide MrgprC agonist (compound 58) both attenuated neuropathic pain in rats and in wild type mice. However, BAM 8-22 lost this analgesic action on neuropathic pain in Mrpgr mutant mice. Using complementary behavioral, electrophysiological, and molecular biological approaches, we aim to assess the therapeutic value of MrgprC as a novel target in the treatment of neuropathic pain, and importantly, to examine the cellular and molecular mechanisms underlying MrgprC-mediated pain inhibition. Specifically, Aim 1 will characterize in detail the effects of intrathecal administration of the two MrgprC agonists on tactile allodynia, mechanical hyperalgesia, heat hyperalgesia and spontaneous pain in rats after an L5 spinal nerve injury. We will then examine whether MrgprC siRNA treatment reduces the analgesic efficacy of BAM 8-22. We will also investigate whether an early intervention with BAM 8-22 prolongs attenuation of neuropathic pain, enhances morphine analgesia in neuropathic pain, and prevents postsurgical pain in rats.
In Aim 2, we will employ in vitro electrophysiological and molecular biological approaches to study the cellular and molecular mechanisms underlying MrgprC-mediated pain inhibition in the dorsal root ganglion (DRG) neurons. We will use both loss-of-function and gain-of-function strategies to determine if MrgprC activation attenuates high-voltage-gated (HVA) calcium current in DRG cells. We will further determine whether nerve injury up regulates the expression and function of MrgprC in uninjured DRG neurons.
In Aim 3 we will study the neurophysiologic basis for MrgprC-mediated pain inhibition in the central nervous system. We will conduct in vivo electrophysiological studies to determine if MrgprC agonist attenuates dorsal horn neuronal sensitization to repetitive noxious inputs and normalizes the established neuronal hyperexcitability induced by the nerve injury. We will investigate whether nerve injury alters the expression of BAM 22, an endogenous Mrgpr ligand, in spinal cord and in DRGs. We postulate that MrgprC agonists may function as anti-hyperalgesic agents during the neuropathic pain state. Because MrgprC is an ortholog to the human MrgprX1, our findings may have important implications for developing new drug leads and mechanism-based treatment strategies for managing neuropathic pain with few side effects.

Public Health Relevance

Our preliminary studies suggest that activation of an important member of Mas-related G protein-coupled receptors, MrgprC, may inhibit neuropathic pain. In this proposal, we will use complementary animal behavioral, electrophysiological, and molecular biological approaches to better assess the therapeutic utility of MrgprC agonist for the treatment of neuropathic pain and to understand the cellular and molecular mechanisms underlying the drug action. Current study may identify a new pain-specific treatment target and lead to a novel mechanism-based approach to the treatment of neuropathic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Babcock, Debra J
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Johns Hopkins University
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Tiwari, Vineeta; Tiwari, Vinod; He, Shaoqiu et al. (2016) Mas-Related G Protein-Coupled Receptors Offer Potential New Targets for Pain Therapy. Adv Exp Med Biol 904:87-103
Yang, Fei; Xu, Qian; Shu, Bin et al. (2016) Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation. Pain 157:2582-2593
Tiwari, Vinod; Yang, Fei; He, Shao-Qiu et al. (2016) Activation of Peripheral μ-opioid Receptors by Dermorphin [D-Arg2, Lys4] (1-4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain. Anesthesiology 124:706-20
Li, Z; He, S-Q; Tseng, P-Y et al. (2015) The inhibition of high-voltage-activated calcium current by activation of MrgC11 involves phospholipase C-dependent mechanisms. Neuroscience 300:393-403
Yang, Fei; Zhang, Chen; Xu, Qian et al. (2015) Electrical stimulation of dorsal root entry zone attenuates wide-dynamic-range neuronal activity in rats. Neuromodulation 18:33-40; discussion 40
Sdrulla, Andrei D; Xu, Qian; He, Shao-Qiu et al. (2015) Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high-threshold afferent inputs in mice. Pain 156:1008-17
Sdrulla, Andrei D; Xu, Qian; He, Shao-Qiu et al. (2015) Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high-threshold afferent inputs in mice. Pain :
Yang, Fei; Zhang, Tong; Tiwari, Vinod et al. (2015) Effects of Combined Electrical Stimulation of the Dorsal Column and Dorsal Roots on Wide-Dynamic-Range Neuronal Activity in Nerve-Injured Rats. Neuromodulation 18:592-7; discussion 598
Tiwari, Vinod; Guan, Yun; Raja, Srinivasa N (2014) Modulating the delicate glial-neuronal interactions in neuropathic pain: promises and potential caveats. Neurosci Biobehav Rev 45:19-27
He, Shao-Qiu; Li, Zhe; Chu, Yu-Xia et al. (2014) MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain. Pain 155:534-44

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