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（由适用提供）：尽管基于MRI的技术为偏头痛所涉及的大脑区域的功能提供了见解，但对这种疾病过程中影响的HE分子机制几乎没有理解。在体内了解这一过程对于确定偏头痛持续和缓解的系统至关重要，尤其是μ-阿皮德基系统，这可以说是大脑中主要的内源性疼痛调节系统之一。使用正面发射断层扫描（PET）和针对μ阿片受体（μOR）的选择性放射性筛查器[11c] carfentanil的最新研究表明，在thalamus和其他疼痛区域中，μOR的可用性降低了（不可移离可结合的bpnd）在thalamus和其他疼痛范围内的迁移率（非头痛（发作）阶段。丘脑是（非）不受欢迎的输入的前脑中的主要继电器结构，该结构将随后分配给多个皮质区域，以进行歧视，认知和情感处理。不幸的是，如果没有引起多种不良反应和功能障碍，外源阿片类药物无法选择性地靶向那些功能失调的大脑区域。实际上，长期的阿片类药物疗法与偏头痛和后悔有关。有趣的是，我们最近的研究还表明，使用非侵入性工具（即经颅直流电流模拟（TDC））可以准确地对这种μ阿片机制进行调节，并且它可以在慢性偏头痛和其他三方疼痛疾病中产生止痛的后效应。但是，由其最常规的镇痛单打产生的电场广泛遍布整个大脑，缺乏直接靶向疼痛相关的结构的特异性。最近，我们组基于硬膜外M1仿真原理创建的一种新型的高清TDC（HD-TDCS）Monortage（Villamar等人，2013年），在慢性深膜疼痛患者中创建了基于硬膜外M1模拟原理，从而仅降低了“对侧”感觉歧视性临床疼痛度量（疼痛强度/面积）。因此，我们研究的主要目标是：首先，与健康对照组相比，偏头痛患者和异常性异常体内的μ-阿片类功能障碍；其次，确定10个非侵入性和精确的M1 HD-TDC的每日课程是否对偶发性偏头痛患者的临床和实验性疼痛度量具有调节作用；第三，为了研究重复的活性M1 HD-TDC是否诱导/恢复丘脑和其他与疼痛相关的区域的μorBPND变化，以及这些变化是否与偏头痛疼痛指标相关。上面的研究代表了偏头痛研究中范式的变化，因为我们直接研究并调节体内最重要的内源性镇痛机制之一。