Peripheral Receptor Mechanisms in Orofacial Muscle Pain

描述（由申请人提供）：与颞下颌关节疾病相关的慢性肌肉疼痛的病理生理学仍然知之甚少。这项研究将阐明外周受体机制在颅面肌痛和痛觉过敏中的重要性。具体而言，我们建议，外周兴奋性氨基酸（EAA）和神经激肽（NK）受体是在诱导三叉神经中枢神经元的神经可塑性变化和肌肉痛觉过敏的发展的关键组成部分。为了调查我们的建议，两个研究目标的构建，每个有几个工作假设。我们将使用行为，免疫细胞化学和电生理的方法来验证这些假设。在目的1中，我们将研究外周EAA受体对中枢敏化和肌肉痛觉过敏产生的贡献。在此目的下的具体假设是（1）在实验性肌炎条件下，外周NMDA和非NMDA谷氨酸受体的阻断对Vc中神经元活化的影响不同，（2）肌内注射谷氨酸将诱导Vc神经元的中枢敏化，拮抗外周EAA受体将阻止谷氨酸诱导的敏化，（3）阻断外周EAA受体可显著减轻实验性肌炎后的肌肉疼痛和痛觉过敏。目的2：研究外周神经激肽受体在中枢敏化和肌肉痛觉过敏中的作用，以及外周EAA和NK受体在肌肉痛觉过敏中的相互作用。具体的假设是（4）阻断NK 1或NK 2受体将不同地影响炎症诱导的Vc中的神经元活化，（5）用NK 1或NK 2受体拮抗剂局部处理将防止炎症诱导的Vc神经元的敏化，（6）阻断外周NK 1或NK 2受体将显著地减少炎症诱导的肌肉痛觉过敏，（7）外周EAA和NK受体两者的阻断将减少Vc中炎症诱导的c-fos表达，其程度大于仅阻断每种受体类型所产生的程度，和（8）外周EAA和NK受体两者的阻断将减少肌肉痛觉过敏，其程度大于仅阻断每种受体类型所产生的程度。这些研究将有助于了解慢性口面部肌肉疼痛的病理生理学，并为新的治疗方式的发展提供直接的见解。

DESCRIPTION (provided by applicant): The pathophysiology of chronic muscle pain associated with temporomanibular disorders is still poorly understood. This research will elucidate the importance of peripheral receptor mechanisms in craniofacial muscle pain and hyperalgesia. Specifically, we propose that peripheral excitatory amino acid (EAA) and neurokinin (NK) receptors are critical components in inducing neuroplastic changes in central trigeminal neurons and the development of muscle hyperalgesia. To investigate our proposal, two research aims are constructed, each with several working hypotheses. We will use behavioral, immunocytochemical and electrophysiological approaches to test these hypotheses. In Aim 1, we will study the contribution of peripheral EAA receptors for the generation of central sensitization and muscle hyperalgesia. Specific hypotheses under this Aim are (1) Blockade of peripheral NMDA and non-NMDA glutamate receptors differentially affect neuronal activation in the Vc under an experimental myositis condition, (2) Intramuscular injections with glutamate will induce central sensitization ofVc neurons and antagonizing peripheral EAA receptors-will prevent the glutamate-induced sensitization, (3) Blockade of peripheral EAA receptors will significantly reduce muscle pain and hyperalgesia following experimental myositis. In Aim 2, we will study (a) the contribution of peripheral neurokinin receptors for the generation of central sensitization and muscle hyperalgesia, and (b) the interaction between peripheral EAA and NK receptors in generation of muscle hyperalgesia. Specific hypotheses are (4) Blockade ofNKl or NK2 receptor will differentially affect the inflammation^inducedneuronal activation in the Vc, (5) Local treatment with NK1 or NK2 receptor antagonist will prevent the, inflammation-induced sensitization of Vc neurons, (6) Blockade of peripheral NKl or NK2 receptor will significantly reduce the inflammation-induced muscle hyperalgesia, (7) Blockade of both peripheral EAA and NK receptors will reduce the inflammation-induced c-fos expression in the Vc greater than that produced by the blockade of each receptor type only, and (8) Blockade of both peripheral EAA and NK receptors will reduce the muscle hyperalgesia greater than that produced by the blockade of each receptor type only. These studies will contribute to understanding the pathophysiology of chronic orofacial muscle pain and provide direct insights for the development of new treatment modalities.