PERIPHERAL NMDA RECEPTORS AND TMD PAIN MECHANISMS

描述(申请人提供)：对包括类风湿性关节炎(RA)和颞下颌关节紊乱病在内的颞下颌关节紊乱病的病因和发病机制了解甚少。我们发现，咀嚼肌或TMJ组织中外周谷氨酸水平的人为升高，在大鼠脑干尾侧亚核引起伤害性传入放电和颌骨反射，并在人类引起疼痛；谷氨酸的反应存在性别差异。这导致了一种普遍的假设，即外周NMDA受体的激活可能与咬肌或TMJ疼痛有关，女性在TMJ疾病中占主导地位。为了解决这一问题，我们将测试(A)通过激活外周NMDA受体并被外周应用NMDA受体拮抗剂阻断的谷氨酸对大鼠咬肌或TMJ的刺激是否可以兴奋大鼠咬肌或TMJ，以及这些作用是否存在性别相关的差异，这依赖于性类固醇激素；(B)大鼠咬肌或TMJ的谷氨酸水平是否因刺激咀嚼肌或TMJ传入而升高，以及这些水平是否存在性别相关的差异，这些水平依赖于性类固醇激素；(C)谷氨酸诱导的咬肌或TMJ外周NMDA受体的激活是否增强了大鼠尾侧伤害性神经元的兴奋性，并被外周应用的NMDA受体拮抗剂阻断，以及这种兴奋性是否存在性别差异，这种增加有赖于性类固醇激素；。(D)如果将谷氨酸注入人的咬肌或TMJ，通过激活外周NMDA受体引起人类疼痛，以及在这些健康受试者中，这种作用以及外周NMDA受体拮抗剂阻断谷氨酸诱导的疼痛的效果是否存在差异，以及对于依赖性激素的RA或肌筋膜TMD患者持续的临床疼痛，是否存在与性别相关的差异；以及(E)如果健康受试者和患者之间的人体咀嚼肌或TMJ谷氨酸水平存在差异，以及依赖性类固醇激素的外周谷氨酸水平是否存在性别相关的差异。通过我们的多学科研究获得的见解将有助于更好地了解肌肉骨骼疼痛的机制，并可能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.