This project investigates peripheral neural mechanisms that underlie the development of mechanical hyperalgesia;a prominent clinical feature associated with persistent muscle pain conditions. We have previously shown that peripherally localized NMDA receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) are important components in evoking acute muscle nociception as well as mechanical hyperalgesia. Several members of the transient receptor potential (TRP) family, particularly TRPV1 and TRPA1, also play an essential role in the development of mechanical hypersensitivity under various pain conditions. Since activation of peripheral glutamate receptors invokes various intracellular signaling cascades leading to nociceptor sensitization, and both TRPV1 and TRPA1 are suggested to function as 'inflammatory signal integrators', we propose that NMDAR/mGluR5 and TRPV1/TRPA1 functionally interact and that activation of NMDAR/mGluR5 leads to TRPV1/TRPA1-dependent mechanical hyperalgesia via multiple intracellular signaling pathways.
Aim1 evaluates functional interactions between NMDAR/mGluR5 and TRPV1/TRPA1 with behavioral pharmacology and in vivo RNAi studies, and provides the morphological and biochemical bases for the interactions between the two receptor systems in trigeminal ganglia (TG). Experiments proposed under Aim2 investigate specific intracellular signaling pathways underlying NMDAR/mGluR5 and TRPV1 interactions, and Aim3 examines intracellular signaling mechanisms unique for NMDAR/mGluR5 and TRPA1 interactions. The integrated studies proposed here will provide comprehensive information on novel mechanisms of peripherally mediated mechanical hyperalgesia, and have immediate translational implications in a relatively understudied area of clinical muscle pain conditions, such as temporomandibular disorders.

Public Health Relevance

This project examines cellular and molecular mechaisms that link two receptor-channel systems that have been independently implicated in muscle pain and hyperalgesia. Peripherally localized glutamate receptors such as NMDA and type I metabotropic glutamate receptors are being increasingly recognized as critical components in mediating the development of pathological pain conditions. We have convincing preliminary evidence that these glutamate receptors functionally interact with TRPV1 and TRPA1, members of the transient receptor potential family, and that interactions between the two types of receptor systems are important elements for mechanical hyperalgesia arising from craniofacial msucle tissue. Therefore, outcomes of this project can offer important new insights in the development of pathologic muscle pain conditions and mechanism-based treatment strategies that can be directed at the peripheral receptor systems to ameliorate persistent orofacial muscle pain conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016062-09
Application #
8434761
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2004-08-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$338,582
Indirect Cost
$112,861
Name
University of Maryland Baltimore
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Chung, M-K; Cho, Y S; Bae, Y C et al. (2014) Peripheral G protein-coupled inwardly rectifying potassium channels are involved in ýý-opioid receptor-mediated anti-hyperalgesia in rat masseter muscle. Eur J Pain 18:29-38
Wang, Sen; Lee, Jongseok; Ro, Jin Y et al. (2012) Warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Mol Pain 8:22
Chung, M-K; Lee, J; Duraes, G et al. (2011) Lipopolysaccharide-induced pulpitis up-regulates TRPV1 in trigeminal ganglia. J Dent Res 90:1103-7
Chun, Yang H; Ro, Jin Y (2010) Electrophysiological characterization of the rat trigeminal caudalis (Vc) neurons following intramuscular injection of capsaicin. Neurosci Lett 469:289-93
Ro, Jin Y; Lee, Jong-Seok; Zhang, Youping (2009) Activation of TRPV1 and TRPA1 leads to muscle nociception and mechanical hyperalgesia. Pain 144:270-7
Chun, Yang-Hyun; Frank, Dorie; Lee, Jong-Seok et al. (2008) Peripheral AMPA receptors contribute to muscle nociception and c-fos activation. Neurosci Res 62:97-104
Ro, Jin Y; Capra, Norman F; Lee, Jong-Seok et al. (2007) Hypertonic saline-induced muscle nociception and c-fos activation are partially mediated by peripheral NMDA receptors. Eur J Pain 11:398-405
Lee, Jongseok; Ro, Jin Y (2007) Differential regulation of glutamate receptors in trigeminal ganglia following masseter inflammation. Neurosci Lett 421:91-5
Lee, J-S; Ro, J Y (2007) Peripheral metabotropic glutamate receptor 5 mediates mechanical hypersensitivity in craniofacial muscle via protein kinase C dependent mechanisms. Neuroscience 146:375-83
Ro, Jin Y; Capra, Norman F (2006) Assessing mechanical sensitivity of masseter muscle in lightly anesthetized rats: a model for craniofacial muscle hyperalgesia. Neurosci Res 56:119-23