Many traditional analgesics have insufficient efficacy, and therefore continued research is of high importance. Recently, we have developed a hypothesis for peripheral cannabinoid antihyperalgesia/antiallodynia via ionotropic cannabinoid receptors. We propose to test the central hypothesis that peripheral cannabinoid antihyperalgesia/ antiallodynia is mediated, at least in part, by peripheral ionotropic receptors. Our original preliminary data demonstrated that application of cannabinoids to sensory neurons leads to: 1) activation of protein phosphatase 2B (i.e., calcineurin); 2) dephosphorylation of TRPV1; and 3) inhibition of TRPV1 activity in a fashion reversed by calcineurin antagonists. Since the original submission, we have discovered that arachidonyl-2-chloroethylamide (ACEA) selectively activates TRPV1 in transfected CHO cells, whereas WIN selectively activates TRPA1, and that AM1241 preferentially activates a heretofore unreported TRPV1/TRPA1 heteromultimer. Although these cannabinoids differ in their activation of TRP channels, they share the ability to desensitize multiple TRP channels and this may be an important property in peripheral analgesia. Moreover, peripheral cannabinoid antihyperalgesia in rats is blocked by a calcineurin antagonist, suggesting that these peripheral effects might be mediated, in part, by ionotropic receptors.
Specific Aim #1; Determine whether cannabinoid pretreatment activates specific calcineurin catalytic subunits(Aa, Ap, or Ay) leading to dephosphorylation of TRPVI or TRPA1.
Specific Aim #2 : Determine whether TRPV1 is required to mediate the peripheral antihyperalgesic/antiallodynic effects of certain cannabinoids.
Specific Aim #3 : Determine whether TRPA1 is required to mediate the peripheral antihyperalgesic/antiallodynic effects of certain cannabinoids. If the hypothesis of ionotropic receptors mediating peripheral cannabinoid antihyperalgesia/antiallodynia is confirmed, then we believe that it will be an important and conceptually innovative discovery for several reasons: First, this is the first demonstration of a functional implication of ionotropic receptors for peripheral cannabinoid antihyperalgesia/antiallodynia. Second, identification of cannabinoid modulation of pain via TRPchannels provides a rationale for a novel class of analgesics that are devoid of classical cannabinoid side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019585-03
Application #
7367115
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Purohit, Vishnudutt
Project Start
2006-03-15
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$277,861
Indirect Cost
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
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
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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
Loyd, D R; Chen, P B; Hargreaves, K M (2012) Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat. Neuroscience 203:207-15
Hargreaves, Kenneth M (2011) Orofacial pain. Pain 152:S25-32
Ruparel, Nikita B; Patwardhan, Amol M; Akopian, Armen N et al. (2011) Desensitization of transient receptor potential ankyrin 1 (TRPA1) by the TRP vanilloid 1-selective cannabinoid arachidonoyl-2 chloroethanolamine. Mol Pharmacol 80:117-23
Patil, Mayur; Patwardhan, Amol; Salas, Margaux M et al. (2011) Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 61:778-88
Patwardhan, Amol M; Akopian, Armen N; Ruparel, Nikita B et al. (2010) Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents. J Clin Invest 120:1617-26

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