Investigation and Modulation of the Mu-Opioid Mechanism in Chronic TMD (in vivo)

Mu-阿片类药物机制在慢性 TMD 中的研究和调节（体内）

• 批准号: 9323372
• 负责人: ALEXANDRE DASILVA
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323372
• 关键词: Absence of pain sensation; Address; Affective; Analgesics; Area; Binding; Brain; Chronic; Clinical; Cognitive; Contralateral; Data; Disease; Electrodes; Evolution; Functional disorder; Goals; High Prevalence; Investigation; Joints; Larrea; Magnetic Resonance Imaging; Measures; Mediating; Methods; Molecular; Motor Cortex; National Institute of Dental and Craniofacial Research; Nature; Neuronal Plasticity; Operative Surgical Procedures; Opioid; Opioid Receptor; Pain; Pain Disorder; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Prosencephalon; Questionnaires; Regulation; Reporting; Research; Research Personnel; Scanning; Sensory; Solid; Specificity; Stress; Structure; Symptoms; System; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Testing; Thalamic structure; Trigeminal Pain; United States National Institutes of Health; base; carfentanil; central pain; conventional therapy; electric field; experience; follow-up; mu opioid receptors; neuromechanism; neuroregulation; neurotransmission; novel; public health relevance; radiotracer; tool; transmission process

 DESCRIPTION (provided by applicant) Approximately 10% of TMD patients will not experience an improvement of their symptoms and around 75% of patients who fail to respond to conservative treatments are also not suitable for TM joint surgery. Initial studies from our NIH NIDCR R56 project using positron emission tomography (PET) with [11C] Carfentanil, a selective radiotracer for μ-opioid receptor (μOR), have demonstrated that there is a decrease in thalamic µOR availability (non-displaceable binding potential BPND) in the brains of TMD patients during masseteric pain compared to healthy controls. μ-opioid neurotransmission is arguably one of the mechanisms most centrally involved in pain regulation and experience. Moreover, the thalamus is the major relay structure in the forebrain for (non)-noxious inputs, which will be distributed subsequently to multiple cortical areas for discriminative, cognitive and affective processing. MRI-based reports have found that those findings co-localize with neuroplastic changes in trigeminal pain patients. Conventional therapies are unable to selectively target the thalamus and associated regions, and there is a paucity of data on how to reverse neuroplastic molecular mechanisms when available medications fail. Interestingly, several studies with motor cortex stimulation (MCS) have shown that epidural electrodes in the primary motor cortex (M1) are effective in providing analgesia in patients with central pain, and that it occurs via indirect modulation of thalamic activity. Evidently, the invasive nature of sucha procedure limits its indication to highly severe pain disorders. New non-invasive neuromodulatory methods for M1, such as transcranial direct current stimulation (tDCS), can now safely modulate the µOR system, providing relatively lasting pain relief in pain patients. Recently, a novel high-definition tDCS (HD-tDCS) montage created by our group was able to reduce exclusively "contralateral" sensory- discrimative clinical pain measures (intensity/area) in TMD patients by targeting precisely the M1 region. Therefore, the main goals of our study are: First, to exploit the μ-opioidergic dysfunction in vivo in TMD patients compared to healthy controls; Second, to determine whether 10 daily sessions of non- invasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in TMD patients; and Third, to investigate whether repetitive active M1 HD-tDCS induces/reverts μOR BPND changes in the thalamus and other pain-related regions, and whether those changes are correlated with TMD pain measures. The studies above represent a change in paradigm in TMD research, as we directly investigate and modulate in vivo one of the most important endogenous analgesic mechanisms in the brain.

 描述（由申请人提供） 大约 10% 的 TMD 患者的症状不会得到改善，大约 75% 对保守治疗无效的患者也不适合进行 TM 关节手术。 NIDCR R56 项目使用正电子发射断层扫描 (PET) 和 [11C] 卡芬太尼（μ-阿片受体 (μOR) 的选择性放射性示踪剂），已证明大脑中丘脑 μOR 的可用性（不可替代结合电位 BPND）下降与健康对照组相比，TMD 患者在咬肌疼痛期间的变化是有争议的，是与疼痛调节和体验最重要的机制之一。此外，丘脑是前脑中用于（非）有害输入的主要中继结构，这些输入随后将分布到多个皮质区域以进行辨别、认知和处理。 基于 MRI 的报告发现，这些发现与三叉神经疼痛患者的神经塑性变化共存，并且无法选择性地针对丘脑和相关区域，并且缺乏关于如何逆转神经塑性分子机制的数据。当可用的药物无效时，一些运动皮层刺激 (MCS) 的研究表明，初级运动皮层 (M1) 中的硬膜外电极可以有效地为中枢性疼痛患者提供镇痛，并且确实会发生这种情况。显然，这种手术的侵入性性质限制了其对 M1 的新非侵入性神经调节方法，例如经颅直流电刺激 (tDCS)，现在可以安全地调节 µOR 系统。 ，为疼痛患者提供相对持久的疼痛缓解，最近，我们小组创建的一种新型高清 tDCS (HD-tDCS) 蒙太奇能够专门减少“对侧”感觉-区分性临床疼痛测量（强度/面积） 因此，我们研究的主要目标是：首先，与健康对照相比，探索 TMD 患者体内的 μ-阿片能功能障碍；其次，确定每天 10 次的非侵入性治疗是否有效。精确的 M1 HD-tDCS 对 TMD 患者的临床和实验疼痛测量具有调节作用；第三，研究重复主动 M1 HD-tDCS 是否诱导/恢复丘脑的 μOR BPND 变化；以及其他与疼痛相关的区域，以及这些变化是否与 TMD 疼痛测量相关。上述研究代表了 TMD 研究范式的变化，因为我们直接研究和调节大脑中最重要的内源性镇痛机制之一。