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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS070814-01A1
Application #
8105635
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Porter, Linda L
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$287,000
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Stephens, Kimberly E; Chen, Zhiyong; Sivanesan, Eellan et al. (2018) RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation. Mol Pain 14:1744806918817429
Yang, Fei; Anderson, Michael; He, Shaoqiu et al. (2018) Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current. Sci Adv 4:eaaq1438
Sdrulla, Andrei D; Guan, Yun; Raja, Srinivasa N (2018) Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. Pain Pract 18:1048-1067
Huang, Qian; Duan, Wanru; Sivanesan, Eellan et al. (2018) Spinal Cord Stimulation for Pain Treatment After Spinal Cord Injury. Neurosci Bull :
Sivanesan, Eellan; Maher, Dermot P; Raja, Srinivasa N et al. (2018) Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future. Anesthesiology :
Tiwari, Vinod; Anderson, Michael; Yang, Fei et al. (2018) Peripherally Acting ?-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats. Anesthesiology 128:1220-1236
He, Shao-Qiu; Xu, Qian; Tiwari, Vinod et al. (2018) Oligomerization of MrgC11 and ?-opioid receptors in sensory neurons enhances morphine analgesia. Sci Signal 11:
Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J et al. (2018) Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy. Neuromodulation 21:10-18
Sun, Shuohao; Xu, Qian; Guo, Changxiong et al. (2017) Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord. Neuron 93:840-853.e5
Li, Zhe; Tseng, Pang-Yen; Tiwari, Vinod et al. (2017) Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain. Proc Natl Acad Sci U S A 114:E1996-E2005

Showing the most recent 10 out of 35 publications