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)
Type
Research Project (R01)
Project #
5R01DE016062-10
Application #
8628107
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Other Basic Sciences
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Chung, Man-Kyo; Lee, Jongseok; Joseph, John et al. (2015) Peripheral group I metabotropic glutamate receptor activation leads to muscle mechanical hyperalgesia through TRPV1 phosphorylation in the rat. J Pain 16:67-76
Asgar, J; Zhang, Y; Saloman, J L et al. (2015) The role of TRPA1 in muscle pain and mechanical hypersensitivity under inflammatory conditions in rats. Neuroscience 310:206-15
Wang, Sen; Joseph, John; Ro, Jin Y et al. (2015) Modality-specific mechanisms of protein kinase C-induced hypersensitivity of TRPV1: S800 is a polymodal sensitization site. Pain 156:931-41
Chung, M-K; Asgar, J; Lee, J et al. (2015) The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia. Neuroscience 297:160-9
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
Joseph, John; Wang, Sen; Lee, Jongseok et al. (2013) Carboxyl-terminal domain of transient receptor potential vanilloid 1 contains distinct segments differentially involved in capsaicin- and heat-induced desensitization. J Biol Chem 288:35690-702
Saloman, J L; Chung, M-K; Ro, J Y (2012) P2X(3) and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons. Neuroscience :
Lee, Jongseok; Saloman, Jami L; Weiland, Gustave et al. (2012) Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle. Pain 153:1514-24
Wang, Sen; Lee, Jongseok; Ro, Jin Y et al. (2012) Warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Mol Pain 8:22
Lee, Jongseok; Chung, Man-Kyo; Ro, Jin Y (2012) Activation of NMDA receptors leads to phosphorylation of TRPV1 S800 by protein kinase C and A-Kinase anchoring protein 150 in rat trigeminal ganglia. Biochem Biophys Res Commun 424:358-63

Showing the most recent 10 out of 18 publications