Sex Steroids, and TMJ Pain

性类固醇和颞下颌关节疼痛

• 批准号: 6921100
• 负责人: LARRY L BELLINGER
• 金额: $ 36.38万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921100
• 关键词: behavior test; biological models; estradiol; estrogens; ganglions; gender difference; gene environment interaction; gene expression; hormone regulation /control mechanism; joints; laboratory rat; male castration; microarray technology; neurogenetics; neuropharmacology; oral facial pain; ovariectomy; progesterone; protein quantitation /detection; sex hormones; temporomandibular joint syndrome; testosterone; trigeminal nerve

DESCRIPTION: The long term goal of this study is to determine the impact of gender differences and sex hormones on gene(s) and molecular pathways leading to and effecting acute and persistent joint pain as observed in the temporomandibular joint (TMJ) and associated peripheral tissues. The objective of this application is to determine the peripheral effect that steroid sex hormones have on acute pain and identify nociception gene(s) that function in pain pathways as modeled in the TMJ. Our central hypothesis is that changes in physiological estrogen, progesterone and testosterone concentrations modulates acute pain as modeled in the TMJ through action at peripheral tissue(s) within and surrounding the joint and/or within the trigeminal ganglia. To test our central hypothesis and attain the objective of this application we propose the following two Specific Aims first, we will characterize pain in the TMJ and surrounding region related to endogenous and administered estrogen and progesterone in females. Second, we will characterize gender differences in pain in the TMJ and surrounding region by determining the modulatory effect of sex steroids in males. The working hypothesis for Specific Aim one is that cyclical plasma levels of estrogen and/or progesterone in females modulates TMJ pain, in part, through changes in gene expression in the joint and/or trigeminal ganglia. To test the working hypothesis the experimental approach will consist of injecting complete Freund's adjuvant (CFA) into the superior TMJ space. The ovariectomized Sprague-Dawley rats will have been treated with physiological doses of 17-beta estradiol and/or progesterone with and without hormone receptor antagonists. The rats will be first tested for TMJ pain using an established non-invasive behavioral procedure. This test uses the time required to eat a meal (i.e., meal duration), as a behavioral measure of pain. Second, changes in the transcript levels of nearly four thousand genes will be measured in the TMJ and trigeminal ganglia of these treated animals with gene microarrays. Third, candidate gene(s) from the gene array studies that were 1) modulated by hormonal treatment and 2) function in pain related pathways will be further quantitated by real-time PCR, ELISA and/or westerns to measure transcript and protein levels. The working hypothesis for Specific Aim two is that low non-cyclical plasma levels of estrogen and/or high testosterone in the males modulates pain through changes in gene expression in the joint and/or trigeminal ganglia. To test the working hypothesis the experimental approach will consist of measuring pain (i.e., meal duration) on castrated and intact male rats treated with and without estrogen before and after injecting CFA in the TMJ. Upon sacrifice transcript levels will be measured. We expect these data will be used for the evaluation and treatment of gender-related TMJ disorders and for mechanistic studies into hormonal action on joint pain. The rationale for completing these proposed studies is that once the hormones influencing pain sensitivity have been characterized and the gene(s) modulated by these hormonal effects in the joint and trigeminal ganglion identified, targets for pharmaceutical intervention of pain in the TMJ can be pursued.

描述：本研究的长期目标是确定性别差异和性激素对导致和影响颞下颌关节 (TMJ) 和相关外周组织中观察到的急性和持续性关节疼痛的基因和分子途径的影响。本应用的目的是确定类固醇性激素对急性疼痛的外周影响，并识别在 TMJ 建模的疼痛通路中发挥作用的伤害感受基因。我们的中心假设是，生理雌激素、孕激素和睾酮浓度的变化通过关节内和周围和/或三叉神经节内的外周组织的作用，调节颞下颌关节中的急性疼痛。为了测试我们的中心假设并实现本应用的目标，我们首先提出以下两个具体目标，我们将描述与女性内源性和施用雌激素和黄体酮相关的颞下颌关节和周围区域的疼痛。其次，我们将通过确定性类固醇对男性的调节作用来描述颞下颌关节及周围区域疼痛的性别差异。具体目标一的工作假设是，女性雌激素和/或孕激素的周期性血浆水平部分通过关节和/或三叉神经节中基因表达的变化来调节颞下颌关节疼痛。为了测试工作假设，实验方法包括将完全弗氏佐剂 (CFA) 注射到上颞下颌关节空间。切除卵巢的Sprague-Dawley大鼠将用生理剂量的17-β雌二醇和/或黄体酮在有或没有激素受体拮抗剂的情况下进行治疗。首先将使用既定的非侵入性行为程序对大鼠进行颞下颌关节疼痛测试。该测试使用进餐所需的时间（即进餐持续时间）作为疼痛的行为测量。其次，将使用基因微阵列测量这些接受治疗的动物的颞下颌关节和三叉神经节中近四千个基因转录水平的变化。第三，来自基因阵列研究的候选基因（1）通过激素治疗调节和2）在疼痛相关通路中的功能将通过实时PCR、ELISA和/或蛋白质印迹进一步定量，以测量转录物和蛋白质水平。具体目标二的工作假设是，男性中低非周期性血浆雌激素水平和/或高睾酮通过改变关节和/或三叉神经节中的基因表达来调节疼痛。为了测试工作假设，实验方法将包括测量在颞下颌关节中注射 CFA 之前和之后接受和不接受雌激素治疗的去势和完整雄性大鼠的疼痛（即进餐时间）。牺牲后将测量转录水平。我们预计这些数据将用于评估和治疗与性别相关的颞下颌关节紊乱，以及激素对关节疼痛作用的机制研究。完成这些拟议研究的基本原理是，一旦确定了影响疼痛敏感性的激素的特征，并确定了关节和三叉神经节中这些激素作用所调节的基因，就可以寻求药物干预颞下颌关节疼痛的目标。