THE ROLE FOR THE GPR30 RECEPTOR IN INFLAMMATORY PAIN

GPR30 受体在炎性疼痛中的作用

• 批准号: 7997956
• 负责人: JILL C FEHRENBACHER
• 金额: $ 26.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997956
• 关键词: Acute; Affect; Afferent Neurons; Agonist; Attenuated; Behavior; Behavioral; Binding; Calcium; Chemicals; Chronic; Control Animal; Data; Disease; Employee Strikes; Epidemiologic Studies; Estradiol; Estrogen Receptors; Estrogens; Exposure to; Female; G-Protein-Coupled Receptors; Gender; Genomics; Gold; High Prevalence; Immunoblotting; Immunohistochemistry; In Situ Hybridization; In Vitro; Inflammation; Injection of therapeutic agent; Ion Channel; Label; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Nerve; Neurons; Nociception; Nociceptors; Orofacial Pain; Pain; Pattern; Perception; Pharmacology; Play; 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; base; in vivo; inflammatory pain; male; nociceptive response; non-genomic; receptor; receptor expression; research study; sensory system; sex; steroid hormone; therapeutic development

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，女性疼痛性疾病的患病率高于男性。尽管与性别相关的差异很多，但大量证据表明雌激素是疼痛的性别依赖性差异的关键因素，特别是在存在炎症的情况下（参见Fillingim和Ness的综述，2000年）。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，发现雌二醇可以通过非基因组机制激活细胞内信号通路，这一发现开辟了类固醇激素也可能诱导三叉神经元中离子通道或受体的翻译后变化以改变神经元对热、机械或化学刺激的敏感性的可能性。我们的初步数据表明，雌二醇和G-1，GPR 30的特异性激动剂，引起炎症诱导的口面热痛觉过敏的雌性大鼠的增加，但没有影响在盐水注射动物的热敏感性。同样，雌二醇急性治疗增加了炎症外周组织中伤害性神经肽iCGRP的刺激释放，但对非炎症活检组织中的释放没有影响。通过注射具有CFA的触须垫诱导的炎症增加了雌二醇的局部浓度，这表明这种假定的炎症介质在体内以相对高的浓度存在于神经末梢周围。最后，我们证明，不仅雌二醇水平增加炎症，但三叉神经节内的GPR 30受体表达也增加后，从雌性（OVX + E2替代）大鼠分离的三叉神经节中的触须垫炎症。这些数据表明，炎症和雌激素可能相互作用，以促进伤害性信号，并有助于增加女性的疼痛感知。我们将研究的表达和定位的受体在三叉神经节，眶下神经，和触须垫皮肤从控制和发炎的大鼠使用mRNA和蛋白质作为终点。此外，我们将确定GPR 30是否具有功能性的作用，通过在体内的行为研究和在体外的研究，检查三叉神经元的敏感性，在调制伤害感受器的敏感性。由于GPR 30的药理学将其与其他雌激素受体区分开来，因此本文的研究结果可能为开发可以选择性逆转GPR 30活性以减轻炎性疼痛而不影响雌激素对经典受体的作用的治疗方法提供机会。公共卫生相关性这项研究将检查一种新发现的雌激素受体对男性和女性疼痛差异的贡献。在炎症过程中，雌激素和雌性大鼠组织中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增强女性炎症期间的疼痛。