The role of gender and pain remains a major health care problem, and in preliminary studies on this topic, we evaluated the long-term effects of estradiol on gene expression in trigeminal neurons. The results constituted an unexpected discovery that estradiol upregulates prolactin (PRL) more than 40 fold in sensory neurons. Follow-up studies demonstrated that PRL and the PRL receptors (PRL-R) are expressed in sensory neurons of both female and male rats, and that application of capsaicin evokes PRL release from trigeminal sensory neurons. Furthermore, application of exogenous PRL significantly and acutely increases nociceptor responsiveness to capsaicin as measured by inward currents, CGRP exocytosis, accumulation of intracellular calcium levels, and nocifensive behavior. These preliminary data provide strong initial support for a completely new hypothesis of nociceptor regulation by an autocrine/paracrine system containing PRL. Based upon this hypothesis, PRL may serve as a novel hyperalgesic agent in both females and in males. We believe that this discovery has substantial scientific and medical implications, and is highly innovative from a conceptual perspective. Therefore, this project will characterize the mechanisms mediating prolactin effects in female and male rats and will directly test the hypotheses that PRL evokes a rapid increase in the responsiveness sensory neurons to noxious stimuli such as capsaicin.
Our specific aims will:
Specific Aim 1 : Determine the effects of exogenous PRL on capsaicin- and inflammation-induced hyperalgesia/allodynia.
Specific Aim 2 : Determine the mechanisms by which PRL rapidly increases the responsiveness of trigeminal neurons to noxious chemical and thermal stimuli.
Specific Aim 3 : Characterize the stimuli that evoke PRL release in trigeminal sensory neurons from in vitro cultures and from acutely isolated and superfused peripheral terminals. The discovery that trigeminal sensory neurons express both PRL and PRLR, and that application of exogenous PRL significantly and rapidly sensitizes trigeminal nociceptors to noxious stimuli such as capsaicin, provides strong initial support for a completely new and innovative hypothesis of nociceptor regulation by an autocrine/paracrine PRL system, and compounds that block the PRL-R may serve as a novel class of analgesic drugs in gender dependent pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017696-05
Application #
8070425
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2007-08-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$346,655
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
Belugin, Sergei; Diogenes, Anibal R; Patil, Mayur J et al. (2013) Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons. J Biol Chem 288:34943-55
Patil, M J; Green, D P; Henry, M A et al. (2013) Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice. Neuroscience 253:132-41
Patil, Mayur J; Ruparel, Shivani B; Henry, Michael A et al. (2013) Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain. Am J Physiol Endocrinol Metab 305:E1154-64
Akopian, Armen N (2011) Regulation of nociceptive transmission at the periphery via TRPA1-TRPV1 interactions. Curr Pharm Biotechnol 12:89-94
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
Scotland, Phoebe E; Patil, Mayur; Belugin, Sergei et al. (2011) Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia. Eur J Neurosci 34:745-54
Patil, Mayur J; Belugin, Sergei; Akopian, Armen N (2011) Chronic alteration in phosphatidylinositol 4,5-biphosphate levels regulates capsaicin and mustard oil responses. J Neurosci Res 89:945-54
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
Por, Elaine D; Samelson, Bret K; Belugin, Sergei et al. (2010) PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150. Biochem J 432:549-56

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