Inflammation or injury can sensitize nociceptive neurons and the resulting hyperexcitability is thought to mediate increased pain sensation. Although pain typically resolves with time, the mechanisms that promote the return to Dr. g are poorly understood. Dysfunction of such a mechanism could contribute to the persistence of chronic pain, while activation could provide relief from pain. The central hypothesis of this proposal is that peripheral group II metabotropic glutamate receptors (mGluRs) regulate the reversal of nociceptor sensitization and hyperalgesia. This hypothesis will be tested with a combination of anatomical, neurophysiological, and behavioral methods. Two subtypes of group II mGluRs exist, mGluR2 and mGluR3. The specific expression of each subtype within dorsal root ganglia (DRG) will be characterized. We will then determine whether mGluR2 or mGluR3 is necessary for the normal recovery from inflammatory and neuropathic pain using mGluR2 and mGluR3 knockout mice. We propose that group II mGluRs can reverse nociceptor sensitization. To test this, patch-clamp techniques will be used to measure neuronal excitability in sensitized DRG neurons. After pharmacological manipulation of group II mGluRs excitability will be reassessed. Membrane excitability is determined by current flux through ion channels, but it is not clear whether group II mGluRs regulate currents involved in sensitization. Two candidate currents, the tetrodotoxin- resistant Na+ and T-type Ca2+ current will be tested for their ability to be modulated by group II mGluRs in sensitized DRG neurons. We hypothesize that group II mGluRs are involved in the endogenous recovery from hyperalgesia. To test this, we will determine whether positive allosteric modulators of group II mGluRs accelerate the recovery from inflammatory hyperalgesia. Finally, we will determine whether group II mGluRs are capable of relieving ongoing neuropathic pain using an operant conditioning paradigm.

Public Health Relevance

Pain continues to be a major cause of human suffering and the leading reason to seek medical attention. The proposed research is directed at identifying a novel mechanism by which pain is endogenously controlled. An understanding of this mechanism may provide a new a target for the development of pain control therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS076324-02
Application #
8366988
Study Section
Special Emphasis Panel (ZRG1-F02B-M (20))
Program Officer
Babcock, Debra J
Project Start
2011-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$53,042
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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
Park, Sung Il; Brenner, Daniel S; Shin, Gunchul et al. (2015) Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat Biotechnol 33:1280-1286
Valtcheva, Manouela V; Davidson, Steve; Zhao, Chengshui et al. (2015) Protein kinase C? mediates histamine-evoked itch and responses in pruriceptors. Mol Pain 11:1
Valtcheva, Manouela V; Samineni, Vijay K; Golden, Judith P et al. (2015) Enhanced nonpeptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch. J Pain 16:346-56
Davidson, Steve; Copits, Bryan A; Zhang, Jingming et al. (2014) Human sensory neurons: Membrane properties and sensitization by inflammatory mediators. Pain 155:1861-1870
Davidson, Steve; Zhang, Xijing; Khasabov, Sergey G et al. (2012) Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J Neurophysiol 108:1711-23