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THE ROLE FOR THE GPR30 RECEPTOR IN INFLAMMATORY PAIN

GPR30 受体在炎性疼痛中的作用

基本信息

批准号：
7826789
负责人：
JILL C FEHRENBACHER
金额：
$ 15.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-05 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7826789
关键词：
Acute Affect Afferent Neurons Agonist Animals Attenuated Behavior Behavioral Biopsy Chemicals Chronic Control Animal Data Disease Employee Strikes Epidemiologic Studies Estradiol Estrogen Receptors Estrogens Female G-Protein-Coupled Receptors Gender Genomics Gold High Prevalence Immunoblotting In Situ Hybridization In Vitro Inflammation Inflammation Mediators Injection of therapeutic agent Ion Channel Label Mechanics Mediating Messenger RNA Nerve Neurons Neuropeptides Nociception Nociceptors Orofacial Pain Pain Pattern Perception Peripheral Pharmacology Preparation Proteins Publishing Rattus Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Saline Sex Characteristics Signal Pathway Signal Transduction Skin Small Interfering RNA Steroid Receptors Stimulus Structure of trigeminal ganglion Testing Thermal Hyperalgesias Time Tissues Transcript Trigeminal System Trigeminal nerve structure Women&apos s Role allodynia design in vivo inflammatory pain male nociceptive response non-genomic novel orofacial public health relevance receptor receptor expression sensory system sex steroid hormone therapeutic development

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：流行病学研究表明，女性疼痛障碍的患病率高于男性。尽管与性别相关的差异很多，但相当多的证据表明，雌激素是疼痛的性别依赖差异的关键因素，特别是在存在炎症的情况下（见Fillingim和Ness的综述，2000）。许多研究已经调查了雌二醇对伤害性反应的基因组效应；然而，雌二醇可以通过非基因组机制激活细胞内信号通路的发现开启了一种可能性，即类固醇激素也可能诱导三叉神经细胞中离子通道或受体的翻译后变化，从而改变神经元对热、机械或化学刺激的敏感性。我们的初步数据表明，雌二醇和GPR30的特异性激动剂G-1均可引起雌性大鼠炎症诱导的口面部热痛觉过敏增加，但对盐水注射动物的热敏性没有影响。同样，雌二醇的急性治疗增加了炎症周围组织中伤害神经肽iCGRP的刺激释放，但对非炎症活检的释放没有影响。注射含有CFA的振动垫引起的炎症增加了局部雌二醇的浓度，表明这种假定的炎症介质在体内以相对高浓度存在于神经末梢周围。最后，我们证明，不仅雌二醇水平随着炎症升高，而且在雌性（OVX + E2替代）大鼠分离的三叉神经节中，三叉神经节内GPR30受体的表达也在振动垫炎症后增加。这些数据表明，炎症和雌激素可能相互作用，促进伤害性信号传导，并有助于增加女性的疼痛感知。我们将以mRNA和蛋白质为终点，研究三叉神经节、眶下神经和发炎大鼠的振动垫皮肤中受体的表达和定位。此外，我们将通过体内行为研究和三叉神经敏感性的体外研究来确定GPR30是否在调节伤害感受器敏感性方面具有功能作用。由于GPR30的药理学与其他雌激素受体的区别，这里的发现可能为开发治疗方法提供机会，这些治疗方法可以选择性地逆转GPR30的活性，以减轻炎症性疼痛，而不影响雌激素在经典受体上的作用。本研究将研究一种新发现的雌激素受体对男性和女性疼痛差异的影响。在炎症期间，雌性大鼠的组织中雌激素和这些新型受体的数量增加。我们将研究这些增加是否有助于女性炎症期间疼痛的增强。