Chronic pain represents an immense clinical problem, with over 100 million Americans afflicted and an annual price tag exceeding half a trillion dollars according to a recent report from the Institute of Medicine. Although the past decade has seen a tremendous increase in our understanding of the neurobiology of pain and it pain sensitization, little progress has been made in improving therapy. We take the position that this gap in translation is due in part to the lack of studies demonstrating that the biological actions of agens used in preclinical animal studies are targeting the same systems and having similar physiological effects in humans prior to initiating clinical trials. With support from this grant, ver the past eleven years my lab has identified the activation of metabotropic glutamate receptor subtype 2/3 (mGlu2/3) in primary sensory neurons as an attractive target for the development of novel analgesic drugs. Pharmacologic activation of mGlu2/3 promotes analgesia, and in fact mGlu2/3 activation appears to be an endogenous mechanism for the resolution of hyperalgesia. We have further demonstrated that enhancing this pathway by promoting epigenetic upregulation of mGlu2 expression with L-acetyl Carnitine (LAC) therapy or using histone deacetylase (HDAC) inhibitors like SAHA (Vorinostat) can promote resolution of hyperalgesia after never injury. These results are consistent with the hypothesis that enhancing mGlu2/3 signaling pharmacologically or via epigenetic regulation can enhance endogenous mechanisms of resolution of chronic pain. This is particularly exciting due to the fact that mGlu2/3 agonists and mGlu2 positive allosteric modulators are in advanced clinical development, and HDAC inhibitors and LAC can be used in patients currently. In this application, we propose a series of studies that aim to 1) clarify the mechanisms of analgesia of these agents in animal models;2) ask whether tolerance occurs in response to analgesic doses of mGlu2 positive allosteric modulators, and whether epigenetic upregulation of mGlu2 expression can prevent tolerance to mGlu2/3 agonists and PAMs, and 3) provide critical data linking animal studies to human physiology by examining the similarities in mGlu2/3 expression in human vs. mouse dorsal root ganglia, and whether the actions of mGlu2/3 on nociceptor physiology observed in mice is similar in human DRG neurons. In this way, we will provide data critical to effective translation o the preclinical data into new therapies for the treatment of chronic pain.

Public Health Relevance

This proposal seeks to identify the mechanism by which a clinically used analgesic and some potentially new pain medicines exert their effects in animal models. Then, we ask whether the mechanism of analgesia that has been identified in these animal studies is operating in the human nervous system, with the goal of helping to more rapidly bring new analgesic drugs to clinical trials to help patients suffering from chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS042595-11A1
Application #
8507318
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
2001-12-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$485,750
Indirect Cost
$163,853
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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Brenner, Daniel S; Golden, Judith P; Vogt, Sherri K et al. (2014) A dynamic set point for thermal adaptation requires phospholipase C-mediated regulation of TRPM8 in vivo. Pain 155:2124-33
Zammataro, Magda; Sortino, Maria Angela; Parenti, Carmela et al. (2014) HDAC and HAT inhibitors differently affect analgesia mediated by group II metabotropic glutamate receptors. Mol Pain 10:68
Brenner, Daniel S; Vogt, Sherri K; Gereau 4th, Robert W (2014) A technique to measure cold adaptation in freely behaving mice. J Neurosci Methods 236:86-91
Zammataro, Magda; Chiechio, Santina; Montana, Michael C et al. (2011) mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. Mol Pain 7:6
Montana, Michael C; Conrardy, Beth A; Cavallone, Laura F et al. (2011) Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice. Anesthesiology 115:1239-50
Qiu, Chang-Shen; Lash-Van Wyhe, Leanne; Sasaki, Makoto et al. (2011) Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor. Pain 152:1052-60
Golden, Judith P; Hoshi, Masato; Nassar, Mohammed A et al. (2010) RET signaling is required for survival and normal function of nonpeptidergic nociceptors. J Neurosci 30:3983-94
Crawford, Devon C; Moulder, Krista L; Gereau 4th, Robert W et al. (2009) Comparative effects of heterologous TRPV1 and TRPM8 expression in rat hippocampal neurons. PLoS One 4:e8166
Montana, Michael C; Cavallone, Laura F; Stubbert, Kristi K et al. (2009) The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. J Pharmacol Exp Ther 330:834-43

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