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

偏头痛中枢 Mu-阿片机制的研究和调节（体内）

• 批准号: 9147490
• 负责人: ALEXANDRE DASILVA
• 金额: $ 36.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147490
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Affective; American; Analgesics; Area; Binding; Brain; Brain region; Chronic; Clinical; Cognitive; Contralateral; Data; Disease; Economic Burden; Electrodes; Evolution; Functional disorder; Goals; Headache; Investigation; Lead; Life; Magnetic Resonance Imaging; Measures; Mediating; Methods; Migraine; Molecular; Motor Cortex; National Institute of Neurological Disorders and Stroke; Nature; Neuronal Plasticity; Opioid; Opioid Receptor; Pain; Pain Disorder; Pain Threshold; Pain intensity; Patients; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Procedures; Process; Prosencephalon; Questionnaires; Refractory; Regulation; Research; Research Personnel; Scanning; Sensory; Solid; Specificity; Stress; Structure; System; Techniques; Testing; Thalamic structure; Therapeutic Studies; Trigeminal Pain; United States National Institutes of Health; allodynia; base; brain dysfunction; carfentanil; central pain; chronic pain; conventional therapy; electric field; experience; follow-up; functional disability; in vivo; insight; midbrain central gray substance; neuromechanism; neuroregulation; neurotransmission; novel; public health relevance; radiotracer; tool; transmission process

 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.

 描述（由申请人提供）：尽管基于MRI的技术已经提供了对涉及偏头痛的脑区域功能的深入了解，但对这种疾病过程中受影响的分子机制了解甚少。了解体内的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-阿片样物质系统，可以说是大脑中主要的内源性疼痛调节系统之一。我们实验室最近的研究使用正电子发射断层扫描（PET）和μ-阿片受体（μOR）的选择性放射性示踪剂[11 C]卡芬太尼，已经证明在头痛（发作）和非头痛（发作间期）阶段，偏头痛患者丘脑和其他疼痛相关区域的μOR可用性（不可替代的结合电位- μOR BPND）降低。丘脑是前脑中传递（非）伤害性信息的主要结构，这些信息随后将被分配到多个皮层区域进行辨别、认知和情感处理。不幸的是，外源性阿片类药物无法选择性地靶向这些功能障碍的大脑区域，而不会引起多种不良反应和功能障碍。事实上，长期阿片类药物治疗与偏头痛的耐受性和恶化有关。有趣的是，我们最近的研究还表明，这种μ-阿片机制的调节可以使用非侵入性工具，即经颅直流电刺激（tDCS）准确实现，并且它可以在慢性偏头痛和其他三叉神经疼痛疾病中产生镇痛后效应。然而，其最传统的镇痛蒙太奇产生的电场广泛分布在大脑中，缺乏直接针对疼痛相关结构的特异性。最近，一种新的高清晰度tDCS（HD-tDCS）蒙太奇（Village等人，2013年），由我们的小组创建的硬膜外M1刺激原则的基础上减少专门的“对侧”感觉辨别的临床疼痛措施（疼痛强度/面积）的慢性三叉神经疼痛患者。因此，我们研究的主要目标是：首先，与健康对照相比，在偏头痛患者和异常性疼痛中利用体内μ-阿片样物质功能障碍;其次，确定每天10次非侵入性和精确的M1 HD-tDCS是否对发作性偏头痛患者的临床和实验疼痛测量具有调节作用;第三，研究重复活动的M1 HD-tDCS是否诱导/逆转丘脑和其他疼痛相关区域的μOR BPND变化，以及这些变化是否与偏头痛测量相关。上述研究代表了偏头痛研究范式的变化，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。