Our research addresses the cellular and molecular mechanisms that underlie pain hypersensitivity associated with injury and disease. We have been studying the role of the neurotransmitter glutamate (Glu) in the modulation of pain sensitivity in the periphery. Glu is a key inflammatory mediator that is released into peripheral tissues during inflammation, and we have found that G protein-coupled Glu receptors known as metabotropic Glu (mGlu) receptors are expressed in peripheral terminals of nociceptors. In the previous term of this grant, our studies showed that activation of peripheral mGluS in nociceptor terminals induces hypersensitivity to thermal and mechanical stimuli. The thermal hyperalgesia can be explained, at least in part, by PKA-dependent sensitization of the heat-sensing protein, TRPV1. We showed that PKA and PKC directly phosphorylate TRPV1, and identified phosphorylation sites critical for modulation of TRPV1 by PKA and PKC in heterologous systems. However, differences in the PKA and PKC modulation of TRPV1 in heterologous systems relative to natively expressed TRPV1 call into question whether the same phosphorylation sites are involved. While this TRPV1 modulation can account for regulation of thermal nociception by mGluS, it cannot explain the induction of mechanical hypersensitivity. Preliminary data show that mGluS enhances excitability of nociceptors, and we suggest that this may underlie the induction of mechanical sensitization by mGluS. Our work and the work of others points to an important role of mGluS is mediating pain hypersensitivity, and as a consequence mGluS antagonists are being pursued as a novel class of analgesics. However, recent work has called into question whether mGluS antagonists reduce pain by blocking mGluS or by an """"""""off target"""""""" action. Studies in the present proposal will address the following open questions: 1) What phosphorylation sites mediate sensitization of TRPV1 in native DRG neurons? 2) What is the relative importance of central and peripheral mGluS in pain hypersensitivity? 3) What are the cellular mechanisms that underlie mechanical hypersensitivity induced by activation of peripheral mGluS? These studies will reveal the cellular and molecular mechanisms by which mGluS modulates thermal and mechanical pain sensation, and will clearly define the role of central and peripheral mGluS in the modulation of pain. They may also help promote the development of mGluS antagonists as analgesics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042595-10
Application #
8037011
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Porter, Linda L
Project Start
2001-12-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2011
Total Cost
$325,850
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Carlin, Dan; Golden, Judith P; Mogha, Amit et al. (2018) Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat. eNeuro 5:
Shepherd, Andrew J; Copits, Bryan A; Mickle, Aaron D et al. (2018) Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. J Neurosci 38:7032-7057
Shepherd, Andrew J; Mickle, Aaron D; Golden, Judith P et al. (2018) Macrophage angiotensin II type 2 receptor triggers neuropathic pain. Proc Natl Acad Sci U S A 115:E8057-E8066
DeBerry, Jennifer J; Samineni, Vijay K; Copits, Bryan A et al. (2018) Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation. Front Integr Neurosci 12:5
Sheahan, Tayler D; Siuda, Edward R; Bruchas, Michael R et al. (2017) Inflammation and nerve injury minimally affect mouse voluntary behaviors proposed as indicators of pain. Neurobiol Pain 2:1-12
Samineni, Vijay K; Mickle, Aaron D; Yoon, Jangyeol et al. (2017) Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain. Sci Rep 7:15865
Oetjen, Landon K; Mack, Madison R; Feng, Jing et al. (2017) Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell 171:217-228.e13
Samineni, Vijay K; Yoon, Jangyeol; Crawford, Kaitlyn E et al. (2017) Fully implantable, battery-free wireless optoelectronic devices for spinal optogenetics. Pain 158:2108-2116
Davidson, Steve; Golden, Judith P; Copits, Bryan A et al. (2016) Group II mGluRs suppress hyperexcitability in mouse and human nociceptors. Pain 157:2081-8
Valtcheva, Manouela V; Copits, Bryan A; Davidson, Steve et al. (2016) Surgical extraction of human dorsal root ganglia from organ donors and preparation of primary sensory neuron cultures. Nat Protoc 11:1877-88

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