PERIPHERAL NMDA RECEPTORS AND TMD PAIN MECHANISMS

描述（由申请人提供）：颞下颌关节疾病的病因和发病机制，包括类风湿关节炎（RA）和颞下颌关节疾病，尚不清楚。我们发现，人工升高咬肌或颞下颌关节组织的外周谷氨酸水平可引起大鼠脑干尾侧亚核的伤害性传入放电和颌反射，并引起人类疼痛；与性别相关的差异出现在对谷氨酸的反应中。这导致了一个普遍的假设，即外周NMDA受体的激活可能导致咬肌或TMJ疼痛，并且女性在TMJ疾病中占主导地位。为了解决这个问题，我们将测试(A)是否大鼠伤害性咬肌或TMJ传入纤维可以被谷氨酸应用于咬肌或TMJ，这是通过激活外周NMDA受体介导的，并被外周应用的NMDA受体拮抗剂阻断，以及这些作用是否存在依赖于性类固醇激素的性别相关差异；(B)大鼠咬肌或颞下颌关节的谷氨酸水平是否因咬肌或颞下颌关节事件的兴奋而升高，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)大鼠尾侧痛觉神经元的兴奋性是否通过谷氨酸诱导的咬肌或颞下颌关节外周NMDA受体的激活而增强，并被外周应用的NMDA受体拮抗剂阻断，以及这种兴奋性的增加是否存在依赖于性类固醇激素的性别相关差异；(D)如果将谷氨酸注入人的咬肌或颞下颌关节通过激活外周NMDA受体而引起人的疼痛，并且这种作用和外周NMDA受体拮抗剂阻断这些健康受试者中谷氨酸引起的疼痛的疗效是否存在性别差异，以及依赖性类固醇激素的RA或肌筋膜TMD患者的持续临床疼痛是否存在性别差异；(E)健康人与患者之间咬肌或颞下颌关节谷氨酸水平是否存在差异，以及依赖于性类固醇激素的外周谷氨酸水平是否存在与性别相关的差异。通过多学科研究获得的见解将有助于更好地理解肌肉骨骼疼痛机制，并为开发治疗颞下颌关节疾病疼痛的新方法提供基础。

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.