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

 描述(申请人提供)大约10%的TMD患者的症状不会得到改善，大约75%的保守治疗无效的患者也不适合进行TM关节手术。我们国家卫生研究院的初步研究 NIDCRR56项目使用μ-阿片受体(μOR)的选择性放射性示踪剂[11C]卡芬太尼进行正电子发射断层扫描，发现与健康对照组相比，咀嚼痛期间TMD患者大脑中丘脑的uOR利用率(不可置换结合潜能BPND)降低。μ-阿片类神经传递可以说是疼痛调节和体验中最核心的机制之一。此外，丘脑是前脑中(非)伤害性输入的主要中继结构，随后将其分配到多个皮质区域，以进行辨别、认知和 情感加工。基于MRI的报告发现，这些发现与三叉神经痛患者的神经可塑性变化共同定位。传统的治疗方法无法选择性地针对丘脑及其相关区域，而且在现有药物无效时如何逆转神经再生的分子机制的数据也很少。有趣的是，几项关于运动皮质刺激(MCS)的研究表明，初级运动皮质(M1)的硬膜外电极对中枢性疼痛患者具有有效的止痛作用，而且是通过间接调节丘脑活动来实现的。显然，这种手术的侵入性将其适应症限制在高度严重的疼痛障碍上。治疗M1的新的非侵入性神经调节方法，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，我们团队发明的一种新的高清晰度tdcs(HD-tdcs)蒙太奇能够唯一地减少对侧的临床疼痛测量(强度/面积)。 通过精确定位M1区域来治疗TMD患者。因此，我们这项研究的主要目的是：第一，与健康对照组相比，研究TMD患者体内的μ阿片能功能障碍；第二，确定每天10次无创且精确的M1 HD-TDC治疗对TMD患者的临床和实验疼痛测量是否具有调制作用；以及第三，研究重复激活的M1 HD-TDC是否诱导/逆转丘脑和其他疼痛相关区域的μ或BPND变化，以及这些变化是否与TMD疼痛测量相关联。上述研究代表了TMD研究范式的改变，因为我们直接在体内研究和调节大脑中最重要的内源性止痛机制之一。

 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.