The management of pain remains a major medical problem that is due, at least in part, to an incomplete understanding of the physiologic mechanisms for transduction of noxious stimuli. Both pharmacological and gene deletion studies have demonstrated a pivotal role for TRPV1 (transient receptor potential subtype V1) in inflammatory heat hyperalgesia and thermoregulation and this receptor is expressed in a significant proportion of pain-sensing sensory neurons, termed nociceptors. Interestingly, the precise mechanism(s) for the endogenous activation of TRPV1 remains unknown. In this application, we will evaluate the innovative hypothesis that TRPV1 activities are regulated by endogenous oxidized linoleic acid metabolites (OLAMs). Our preliminary data demonstrate that heat evokes the release of linoleic acid metabolites that comprise a new family of physiologically relevant TRPV1 agonists by contributing to the heat responsiveness of this channel. Based upon previous studies and our own results, we propose the central hypothesis that certain peripheral stimuli trigger the release of OLAMs that regulate TRPV1 activities.
Specific Aim 1 : Determine the key enzymatic pathway(s) involved in the generation of OLAM- induced TRPV1 activation in cultured sensory neurons.
Specific Aim 2 : Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) regulating OLAM-induced TRPV1 activities in control vs inflamed skin biopsies.
Specific Aim 3 : Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) for regulating inflammatory thermal hyperalgesia/allodynia in vivo. This novel hypothesis may have considerable medical significance since mechanisms inhibiting OLAM synthesis or function may comprise novel targets for analgesic drug development. In addition, the discovery of OLAM regulation of TRPV1 activities provides a novel and previously unknown mechanism for pain transduction that may promote fundamental research into cellular transduction of noxious stimuli as well as research on preclinical pain models ranging from inflammation to neuropathic conditions to cancer-related pain.

Public Health Relevance

Increased understanding of pain mechanisms may lead to improved pain management by identifying new approaches for developing analgesic drugs. In this application, we propose to study the role of endogenous oxidized linoleic acid metabolites (OLAMs) in activating an important pain receptor, called TRPV1 (transient receptor potential subtype V1). The proposed studies may have considerable medical significance since drugs that inhibit OLAM synthesis or function may serve as novel analgesics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072890-03
Application #
8334031
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
2010-09-20
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$365,167
Indirect Cost
$120,908
Name
University of Texas Health Science Center San Antonio
Department
Dentistry
Type
Schools of Dentistry
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Eskander, Michael A; Ruparel, Shivani; Green, Dustin P et al. (2015) Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms. J Neurosci 35:8593-603
Ruparel, Shivani; Hargreaves, Kenneth M; Eskander, Michael et al. (2013) Oxidized linoleic acid metabolite-cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain. Pain 154:2363-71
Brandfellner, Heather M; Ruparel, Shivani B; Gelfond, Jonathan A et al. (2013) Major blunt trauma evokes selective upregulation of oxidative enzymes in circulating leukocytes. Shock 40:182-7
Green, Dustin P; Ruparel, Shivani; Roman, Linda et al. (2013) Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury. Pain 154:2512-20
Ruparel, Shivani; Green, Dustin; Chen, Paul et al. (2012) The cytochrome P450 inhibitor, ketoconazole, inhibits oxidized linoleic acid metabolite-mediated peripheral inflammatory pain. Mol Pain 8:73
Ruparel, Shivani; Henry, Michael A; Akopian, Armen et al. (2012) Plasticity of cytochrome P450 isozyme expression in rat trigeminal ganglia neurons during inflammation. Pain 153:2031-9
Hargreaves, Kenneth M (2011) Orofacial pain. Pain 152:S25-32
Loyd, Dayna R; Weiss, Gabriela; Henry, Michael A et al. (2011) Serotonin increases the functional activity of capsaicin-sensitive rat trigeminal nociceptors via peripheral serotonin receptors. Pain 152:2267-76