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。本研究将阐明外周受体机制在颅面肌疼痛和痛觉过敏中的重要性。具体来说，我们提出外周兴奋性氨基酸（EAA）和神经激肽（NK）受体是诱导三叉神经中枢神经元神经可塑性变化和肌肉痛觉过敏发展的关键成分。为了研究我们的建议，我们构建了两个研究目标，每个目标都有几个可行的假设。我们将使用行为、免疫细胞化学和电生理方法来检验这些假设。在Aim 1中，我们将研究外周EAA受体对中枢致敏和肌肉痛觉过敏产生的贡献。本研究的具体假设是：(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神经元激活的影响存在差异；(2)肌内注射谷氨酸会诱导Vc神经元的中枢致敏，并拮抗外周EAA受体，从而阻止谷氨酸诱导的致敏。(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。在Aim 2中，我们将研究(a)外周神经激肽受体对中枢致敏和肌肉痛觉过敏产生的贡献，以及(b)外周EAA和NK受体在肌肉痛觉过敏产生中的相互作用。具体的假设是(4)阻断NKl或NK2受体会对Vc中炎症诱导的神经元激活产生不同的影响，(5)局部使用NK1或NK2受体拮抗剂治疗会阻止炎症诱导的Vc神经元致敏，(6)阻断外周NKl或NK2受体会显著减少炎症诱导的肌肉痛觉过敏。(7)阻断外周EAA和NK受体对Vc中炎症诱导的c-fos表达的抑制作用大于仅阻断每种受体的作用；(8)阻断外周EAA和NK受体对肌肉痛觉过敏的抑制作用大于仅阻断每种受体的作用。这些研究将有助于理解慢性口面肌痛的病理生理学，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.