Epidemiological studies indicate a higher prevalence of painful disorders in females than in males. Although gender-related differences are numerous, considerable evidence implicates estrogens as critical factors in sex-dependent differences in pain, especially in conditions where inflammation is present (see review by Fillingim and Ness, 2000). Numerous studies have investigated the genomic effects of estradiol on nociceptive responses;however, the discovery that estradiol can activate intracellular signaling pathways through non-genomic mechanisms opens up the possibility that the steroid hormone might also induce posttranslational changes of ion channels or receptors in trigeminal neurons to alter the sensitivity of neurons to thermal, mechanical, or chemical stimuli. Our preliminary data indicate that both estradiol and G-1, a specific agonist for the GPR30, elicit increases in inflammation-induced orofacial thermal hyperalgesia in female rats, but have no effect on thermal sensitivity in saline-injected animals. Likewise, acute treatment with estradiol augments the stimulated release of the nociceptive neuropeptide iCGRP from inflamed peripheral tissues, but has no effect on release from noninflamed biopsies. Inflammation induced by injection of the vibrissal pad with CFA augments the local concentration of estradiol, suggesting that this putative inflammatory mediator is present in vivo at relatively high concentrations around the nerve terminals. Finally, we demonstrate that not only are estradiol levels increased with inflammation, but the GPR30 receptor expression within the trigeminal ganglia is also increased subsequent to vibrissal pad inflammation in trigeminal ganglia isolated from female (OVX + E2 replacement) rats. These data suggest that inflammation and estrogen may interact to facilitate nociceptive signaling and contribute to increased pain perception in females. We will examine the expression and localization of the receptor in trigeminal ganglia, infraorbital nerve, and vibrissal pad skin from control and inflamed rats using both mRNA and protein as endpoints. Furthermore, we will ascertain whether the GPR30 has a functional role in modulating nociceptor sensitivity by means of in vivo behavioral studies and in vitro studies examining the sensitivity of trigeminal neurons. Because the pharmacology of the GPR30 distinguishes it from other estrogen receptors, the findings here may provide an opportunity for the development of therapeutics which can selectively reverse GPR30 activity to attenuate inflammatory pain without affecting the actions of estrogens at the classical receptors.

Public Health Relevance

This study will examine the contribution of a newly discovered receptor for estrogens to differences in pain between males and females. During inflammation, there is an increase in the amount of estrogens and of these novel receptors in tissues from female rats. We will examine whether these increases contribute to enhanced pain during inflammation in females.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE018796-03
Application #
7826789
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2009-05-05
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$154,000
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Duarte, Djane B; Vasko, Michael R; Fehrenbacher, Jill C (2012) Models of inflammation: carrageenan air pouch. Curr Protoc Pharmacol Chapter 5:Unit5.6
Fehrenbacher, Jill C; Vasko, Michael R; Duarte, Djane B (2012) Models of inflammation: Carrageenan- or complete Freund's Adjuvant (CFA)-induced edema and hypersensitivity in the rat. Curr Protoc Pharmacol Chapter 5:Unit5.4
Fehrenbacher, Jill C; Sun, Xiaoling X; Locke, Erin E et al. (2009) Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue. Pain 144:253-61