PERIPHERAL NMDA RECEPTORS AND TMD PAIN MECHANISMS

描述（由申请人提供）：颞下颌关节紊乱病（包括类风湿性关节炎（RA）和颞下颌关节紊乱病）的病因和发病机制知之甚少。 我们已经发现，人工升高咬肌或颞下颌关节组织中的外周谷氨酸水平引起伤害性传入放电和下颌反射，涉及大鼠脑干尾侧亚核，并诱导人类疼痛;性别相关的差异发生在谷氨酸的反应。 这导致了一个普遍的假设，即外周NMDA受体的激活可能有助于咬肌或TMJ疼痛和女性在TMJ疾病中的优势。 为了解决这个问题，我们将测试（A）大鼠伤害感受咬肌或TMJ传入纤维是否可以通过对咬肌或TMJ施加谷氨酸而兴奋，谷氨酸通过外周NMDA受体的激活而介导，并被外周施加的NMDA受体拮抗剂阻断，以及这些效应是否存在依赖于性类固醇激素的性别相关差异;（B）大鼠咬肌或TMJ中的谷氨酸水平是否由于咬肌或TMJ传入的兴奋而升高，以及这些水平是否存在依赖于性类固醇激素的性别相关差异;（C）如果大鼠尾侧伤害感受神经元的兴奋性通过咬肌或TMJ中的外周NMDA受体的谷氨酸诱导的激活而增强，并且通过外周应用的NMDA受体拮抗剂而阻断，以及这种兴奋性增加是否存在性别差异，这种差异取决于性类固醇激素;（D）如果将谷氨酸注射到人咬肌或TMJ中通过激活外周NMDA受体而引起人的疼痛，如果这种效应和外周NMDA受体拮抗剂阻断谷氨酸的功效存在性别相关差异，在这些健康受试者中诱发的疼痛以及在依赖性类固醇激素的RA或肌筋膜TMD患者中持续的临床疼痛;和（E））在健康受试者和患者之间是否存在人咬肌或TMJ谷氨酸水平的差异，以及是否存在依赖性类固醇激素的外周谷氨酸水平的性别相关差异。 通过我们的多学科研究获得的见解将导致更好地了解肌肉骨骼疼痛机制，并可以为开发新的方法来管理TMJ疾病的疼痛提供基础。

DESCRIPTION (provided by applicant): The etiology and pathogenesis of temporomandibular joint disorders, including rheumatoid arthritis (RA) and temporomandibular disorders, are poorly understood. We have found that artificial elevation of peripheral glutamate levels in masseter muscle or TMJ tissues evokes nociceptive afferent discharges and jaw reflexes involving brainstem subnucleus caudalis in rats and induces pain in humans; sex-related differences occur in the responses to glutamate. This has led to the general hypothesis that activation of peripheral NMDA receptors may contribute to masseter muscle or TMJ pain and the female predominance in TMJ disorders. To address this, we will test (A) if rat nociceptive masseter or TMJ afferent fibers can be excited by glutamate application to masseter or TMJ that is mediated through activation of peripheral NMDA receptors and blocked by peripherally applied NMDA receptor antagonist, and if there are sex-related differences in these effects that are dependent on sex steroid hormones; (B) if glutamate levels in rat masseter or TMJ are elevated by excitation of masseter or TMJ afferents, and if there are sex-related differences in these levels that are dependent on sex steroid hormones; (C) if the excitability of rat caudalis nociceptive neurons is enhanced by glutamate-induced activation of peripheral NMDA receptors in masseter or TMJ and blocked by peripherally applied NMDA receptor antagonist, and if there are sex-related differences in this excitability increase that are dependent on sex steroid hormones; (D) if injection of glutamate into the human masseter or TMJ evokes pain in humans through activation of peripheral NMDA receptors, and if there are sex-related differences in this effect and in the efficacy of peripheral NMDA receptor antagonist to block glutamate-induced pain in these healthy subjects as well as ongoing clinical pain in RA or myofascial TMD patients that are dependent on sex steroid hormones; and (E)) if there is a difference in human masseter or TMJ glutamate levels between healthy subjects and the patients, and if there are sex-related differences in peripheral glutamate levels that are dependent on sex steroid hormones. Insights gained by our multidisciplinary investigations will lead to a better understanding of musculoskeletal pain mechanisms and could provide a basis for the development of novel approaches for the management of pain in TMJ disorders.