Investigation and Modulation of the Central Mu-Opioid Mechanism in Migraine (in vivo)

 描述(申请人提供)：尽管基于MRI的技术已经为偏头痛涉及的大脑区域的功能提供了洞察力，但对这种疾病过程中受到影响的分子机制知之甚少。在体内了解这一过程对于确定参与偏头痛持续和缓解的系统至关重要，特别是μ阿片能系统，可以说是大脑中主要的内源性疼痛调制系统之一。我们实验室最近使用正电子发射断层扫描结合μ阿片受体(μOR)的选择性放射性示踪剂[11C]卡芬太尼的研究表明，偏头痛患者在头痛(发作期)和非头痛(发作间歇期)期间，丘脑和其他疼痛相关区域的μOR可用性(不可置换结合势-μ或BPND)减少。丘脑是前脑中(非)伤害性输入的主要中继结构，随后将分布到多个皮质区域，进行辨别、认知和情感处理。不幸的是，外源性阿片类药物不能选择性地靶向那些功能失调的脑区，而不会引起多种不良反应和功能损害。事实上，长期的阿片类药物治疗与偏头痛的耐受性和恶化有关。有趣的是，我们最近的研究也表明，通过一种非侵入性的工具，即经颅直流电刺激(TDC)，这种μ-阿片机制的调节可以准确地实现，并且它可以在慢性偏头痛和其他三叉神经疼痛障碍中产生止痛后遗症。然而，其最传统的止痛蒙太奇产生的电场广泛分布在整个大脑中，缺乏直接针对疼痛相关结构的特异性。最近，我们团队基于硬膜外M1刺激原理创建的一种新型高清晰度tDCs(HD-tDCs)蒙太奇(Villamar等人，2013)独家减少了慢性三叉神经痛患者的“对侧”感觉辨别临床疼痛测量(疼痛强度/面积)。因此，我们这项研究的主要目标是：第一，与健康对照组相比，偏头痛患者和痛觉过敏患者体内的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治疗对发作性偏头痛患者的临床和实验疼痛措施是否具有调制作用；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偏头痛疼痛措施有关。上述研究代表了偏头痛研究范式的改变，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): Although MRI-based techniques have provided insights into the function of brain regions involved in migraine, there is little understanding of he molecular mechanisms affected during the course of this disorder. Understanding this process in vivo is crucial to determine the systems involved in the persistence and relief of migraine, especially the μ-opioidergic system, arguably one of the principal endogenous pain modulatory systems in the brain. Recent studies from our lab using positron emission tomography (PET) with a selective radiotracer for μ-opioid receptor (μOR), [11C]carfentanil, have demonstrated that there is a decrease in μOR availability (non-displaceable binding potential - μOR BPND) in the thalamus, and other pain-related regions, in the brains of migraineurs during the headache (ictal) and non-headache (interictal) phases. 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. Unfortunately, exogenous opioids are unable to selectively target those dysfunctional brain regions without inducing multiple adverse effects and functional impairments. In fact, prolonged opioid therapy has been associated with migraine endurance and worsening. Interestingly, our recent studies have also shown that modulation of such μ-opioid mechanisms can be accurately achieved using a noninvasive tool, namely transcranial direct current stimulation (tDCS), and that it can produce analgesic after-effects in chronic migraine and other trigeminal pain disorders. However, the electric fields generated by its most conventional analgesic montage are widely spread across the brain, lacking specificity on the pain-related structures directly targeted. Recently, a novel high-definition tDCS (HD- tDCS) montage (Villamar et al., 2013) created by our group based on epidural M1 stimulation principles reduced exclusively "contralateral" sensory-discriminative clinical pain measures (pain intensity/area) in chronic trigeminal pain patients. Therefore, the main goals of our study are: First, to exploit the μ-opioidergic dysfunction in vivo in migraine patients and allodynia 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 episodic migraine 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 migraine pain measures. The studies above represent a change in paradigm in migraine research, as we directly investigate and modulate in vivo one of the most important endogenous analgesic mechanisms in the brain.