Our long term objectives are to elucidate peripheral receptors that can be targeted to relieve/control pain. We are focusing on metabotropic glutamate receptors (mGluRs), Group III in particular, because they produce inhibition and long term neuronal depression in the CNS. If Group III produces the same inhibitory modulation in the periphery, selective activation of Group III mGluRs on nociceptors may provide powerful and long lasting depression of noxious input. Our central hypothesis is that Group III mGluRs are integral components of peripheral sensory integration. Specifically, we hypothesize that Group III are localized on primary sensory neurons and are co-localized with TRP receptors that participate in heat (TRPV1), mechanical (TRPV4), and cold (TRPA1) transduction (aim 1). We hypothesize that activation of Group III will reduce the heat, mechanical and cold hypersensitivity that accompanies nerve-injury induced (neuropathic) pain and inflammatory pain (aim 2). We will show that the mechanism underlying reduced TRP function is related to inhibition of the cAMP/protein kinase A (PKA) pathway, an effector pathway for Group III mGluRs, as well as TRPV1, TRPV4 and TRPA1 (aim 3). In single and double label experiments, we will co-localize Group III subtypes with TRP channels in dorsal root ganglion cells and digital nerves. Ca2+ imaging studies will demonstrate the functional interaction between the Group IIIs and TRP channels. Behavioral studies and recording studies using a skin- nerve preparation will confirm the presence of Group IIIs on nociceptors and demonstrate that their activation can reduce nociceptor activity in the nerve-injured and inflamed state. The cAMP/PKA pathway will be shown as the common intracellular pathway used by Group III to modulate TRP function. The preliminary data show that Group III mGluRs can effectively reduce behavioral and neuronal responses induced by TRP activation, and relieve neuropathic and inflammatory pain. Understanding the anatomical and functional relationship between Group III mGluRs and TRP channels is critical to identifying new, non-opioid targets/approaches to treatment of chronic pain.

Public Health Relevance

This proposal will test the overall hypothesis that activation of peripheral Group III mGluRs is an effective treatment for nerve-injury and inflammatory pain. If our hypothesis is correct, we are defining novel peripheral targets that when activated reduce peripheral sensitization and thus have functional relevance in the control of pain of peripheral origin. This family of receptors will offer a large array of extracellular and intracellular targets that are different from those associated with Group II mGluRs, and, based on our preliminary data, will be important in the modulation of hyperalgesic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027910-23
Application #
8423026
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Babcock, Debra J
Project Start
1990-01-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
23
Fiscal Year
2013
Total Cost
$371,473
Indirect Cost
$128,680
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Carlton, Susan M (2014) Nociceptive primary afferents: they have a mind of their own. J Physiol 592:3403-11
Yuan, Su-Bo; Shi, Yuqiang; Chen, Jinghong et al. (2014) Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol 75:837-50
Hogan, Dale; Baker, Alyssa L; Moron, Jose A et al. (2013) Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin. Pain 154:2297-309
Carlton, Susan M; Zhou, Shengtai; Govea, Rosann et al. (2011) Group II/III metabotropic glutamate receptors exert endogenous activity-dependent modulation of TRPV1 receptors on peripheral nociceptors. J Neurosci 31:12727-37
Ta, Lauren E; Bieber, Allan J; Carlton, Susan M et al. (2010) Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol Pain 6:15
Carlton, Susan M; Du, Junhui; Zhou, Shengtai (2009) Group II metabotropic glutamate receptor activation on peripheral nociceptors modulates TRPV1 function. Brain Res 1248:86-95
Carlton, Susan M; Du, Junhui; Tan, Huai Yu et al. (2009) Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury. Pain 147:265-76
Ji, G; Zhou, S; Carlton, S M (2008) Intact Adelta-fibers up-regulate transient receptor potential A1 and contribute to cold hypersensitivity in neuropathic rats. Neuroscience 154:1054-66
Du, J; Zhou, S; Carlton, S M (2008) Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states. Neuroscience 154:754-66
Ji, G; Zhou, S; Kochukov, M Y et al. (2007) Plasticity in intact A delta- and C-fibers contributes to cold hypersensitivity in neuropathic rats. Neuroscience 150:182-93