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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Babcock, Debra J
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Washington University
Schools of Medicine
Saint Louis
United States
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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
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
Brenner, Daniel S; Golden, Judith P; Vogt, Sherri K et al. (2015) A simple and inexpensive method for determining cold sensitivity and adaptation in mice. J Vis Exp :
O'Brien, Daniel E; Alter, Benedict J; Satomoto, Maiko et al. (2015) ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival. J Neurosci 35:9491-507
Valtcheva, Manouela V; Davidson, Steve; Zhao, Chengshui et al. (2015) Protein kinase Cδ 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 155:1861-70
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

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