Trigeminal - RVM involvement in bilateral deep tissue orofacial hyperalgesia

描述（由申请人提供）：大约有1000万美国人患有颞下颌关节疾病（TMJD）。尽管口面持续性疼痛在人群中普遍存在，但由于缺乏对所涉及机制的了解，患者的治疗方法很少。最近，有报告显示，肌筋膜TMJD或慢性颈部疼痛的患者在三叉神经区域出现双侧超敏反应。单侧完全弗氏佐剂（CFA）诱导的深部组织炎症导致大鼠双侧口面痛觉过敏。将炎性细胞因子白细胞介素-12（IL-12）单侧注射到三叉神经极间亚核/尾侧亚核（VIVC）过渡区也导致双侧口面痛觉过敏，并且随着延髓头端腹内侧（RVM）的病变而减弱。本研究拟探讨单侧诱导的VIVC神经元细胞因子激活、RVM神经元激活和对侧VIVC神经元激活是否是双侧深部组织口面痛觉过敏发展所必需的。具体目标1将研究VIVC过渡区的单侧IL-12释放是否对双侧口面痛觉过敏的发展是必要的。使用CFA诱导的咬肌炎症模型，在将IL-1受体拮抗剂注射到VIVC过渡区之前和之后测试机械敏感性。具体目标2将调查是否在RVM的NK 1-R激活是必要的双边口面痛觉过敏的发展。将在炎症后RVM内NK 1-R拮抗剂显微注射后测试机械敏感性。免疫组织化学将用于观察可能投射到RVM的各种核中SP表达的变化。具体目标3将研究RVM中的NK 1-R激活是否导致对侧VIVC中的降维能易化。在对侧VIVC中，使用色氨酸羟化酶-2 shRNA从RVM中的神经元中去除5-HT，并且使用特异性拮抗剂Y-25130阻断5-HT 3受体。将测量机械敏感性和Fos蛋白表达以确定5-HT/5-HT 3信号传导在对侧口面痛觉过敏的发展中的参与。通过更好地了解深组织疼痛促进对侧的途径和机制，新的治疗方法和策略可能会开发口面疼痛障碍。!

DESCRIPTION (provided by applicant): Approximately 10 million Americans suffer from temporomandibular joint disorders (TMJD). Despite the prevalence of orofacial persistent pain amongst the population, few treatments exist for patients due to the lack of understanding about the mechanisms involved. Recently, reports have shown that patients with myofascial TMJD or chronic neck pain experience bilateral hypersensitivity in the trigeminal region. Unilateral complete Freund's adjuvant (CFA)-induced deep tissue inflammation leads to bilateral orofacial hyperalgesia in rats. Unilateral injection of the inflammatory cytokine, interleukin-12 (IL-12) into the trigeminal subnuclei interpolaris/caudalis (VIVC) transition zone also results in bilateral orofacial hyperalgesia and is attenuated with lesions to the rostral ventromedial medulla (RVM). This study proposes to investigate whether unilaterally- induced cytokine activation of VIVC neurons, the activation of RVM neurons, and the activation of contralateral VIVC neurons are necessary for the development of bilateral deep tissue orofacial hyperalgesia. Specific aim 1 will investigate whether unilateral IL-12 release in the VIVC transition zone is necessary for the development of bilateral orofacial hyperalgesia. Using a CFA-induced inflammation model of the masseter muscle, mechanical sensitivity will be tested before and after injection of IL-1 receptor antagonist into the VIVC transition zone. Specific aim 2 will investigate whether NK1-R activation in the RVM is necessary for the development of bilateral orofacial hyperalgesia. Mechanical sensitivity will be tested after intra-RVM NK1-R antagonist microinjection following inflammation. Immunohistochemistry will be used to look at changes in SP expression in various nuclei that may project to the RVM. Specific aim 3 will investigate whether NK1-R activation in the RVM leads to descending serotonergic facilitation in the contralateral VIVC. 5-HT will be depleted from neurons in the RVM using tryptophan hydroxylase-2 shRNA and 5-HT3 receptors will be blocked with specific antagonist, Y-25130, in the contralateral VIVC. Mechanical sensitivity and Fos protein expression will be measured to determine the involvement of 5-HT/5-HT3 signaling in the development of contralateral orofacial hyperalgesia. Through better understanding of the pathways and mechanisms involved in deep tissue pain facilitation to the contralateral side, novel therapies and strategies may be developed for orofacial pain disorders. !