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: 10375812
• 负责人: ALEXANDRE DASILVA
• 金额: $ 63.4万
• 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 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375812
• 关键词: Absence of pain sensation; Acute; Affinity; Amygdaloid structure; Analgesics; Basal Ganglia; Bilateral; Binding; Biological; Brain; Cancer Patient; Chronic; Clinic; Clinical; Complex; Data; Disease; Dopamine; Dopaminergic Agents; Electrodes; Emotional; Enkephalins; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Headache; High Prevalence; Home; Intake; Investigation; Life; Limbic System; Link; Measures; Medical; Methods; Migraine; Molecular; Motor Cortex; Neurons; Neurotransmitters; Opioid; Opioid Peptide; Pain; Parkinson Disease; Pathway interactions; Patients; Persistent pain; Pharmaceutical Preparations; Positron-Emission Tomography; Protocols documentation; Raclopride; Recording of previous events; Recurrence; Research; Restless Legs Syndrome; Rewards; Sensory; Severities; Signal Transduction; Solid; Structure; Substance abuse problem; Symptoms; System; Thalamic structure; Trigeminal System; allodynia; associated symptom; base; beta-Endorphin; carfentanil; central pain; clinical application; comorbidity; conventional therapy; dopamine system; emotion regulation; high risk; mu opioid receptors; neuroimaging; neuroregulation; neurotransmission; novel; pain perception; pain relief; radiotracer; sensory system; sex; side effect; somatosensory; uptake

Abstract Episodic migraine (EM) sufferers can develop a progressive state of their disease with more than 15 attacks per month. This state is referred to as chronic migraine (CM), a disorder that significantly impacts a patient’s daily life with more frequent sensory and emotional suffering and potential for substance abuse, especially opiates. Built on rigorous scientific data from our initial R01 on EM, our next goal is to expand the investigation and modulation of endogenous µ-opioid neurotransmission to more complex CM patients. We will investigate how this µ-opioid dysfunction impacts other crucial central neurotransmitters (D2/D3 dopamine) and systems (sensory and reward), leading to a worsening of pain/emotional suffering. The endogenous μ-opioid and D2/D3 dopamine are arguably two of the most crucial molecular mechanisms responsible for pain and emotional regulation; they are the primary targets for the action of the most potent exogenous analgesic and psychotic drugs available. Our initial EM study using PET with [11C] carfentanil, a selective μ-opioid receptor (μOR) radiotracer, has demonstrated a decrease in μOR availability (non- displaceable binding potential [BPND]) in the brains of EM patients during attacks. Notably, our preliminary data shows that with the progression to CM, there is a further increase in μ-opioid (peptide) release in the amygdala that correlates with attack severity and allodynia. The EM attacks were also accompanied by an increase in DA D2/D3 BPND measured by [11C]raclopride in the basal ganglia, and the longer the history and recurrence of attacks, the lower the ictal endogenous DA release. We were the first group to demonstrate that a non-invasive neuromodulatory method targeting the primary motor cortex (M1), transcranial direct current stimulation (tDCS), can immediately modulate the µOR system. We further developed a M1 high-definition tDCS montage (M11 HD-tDCS) that significantly reversed μOR BPND in more frequent EM patients and reduced CM-specific clinical endpoints (e.g., moderate/severe days per month). Built on solid and persuasive data from our prior R01 in EM, our renewal project expands its relevance by directly evaluating and modulating crucial neurotransmitters, systems/symptoms associated with pain suffering in the most resilient migraine, CM: Aim1. Demonstrate with PET that patients who progress to CM display higher dysfunction than EM in endogenous μ-opioid and D2/D3 dopamine neurotransmission that correlates with their attack frequency and severe pain suffering; Aim2. Evaluate the impact of CM on the neuronal systems’ connectivity and BOLD signal variability and their association with dysfunction in neurotransmission and worsening of attacks; Aim3. Investigate whether 20 daily lab/home-based unilateral and bilateral M11-2 HD-tDCS modulation have different effects on the molecular, system, and clinical states in CM patients.

抽象的 情节性偏头痛（EM）患者可以发展其疾病的渐进状态，超过15 每月攻击。该状态被称为慢性偏头痛（CM），这种疾病会对 患者的日常生活具有更常见的感觉和情感痛苦以及滥用药物的潜力， 特别优化。基于我们最初的R01上的严格科学数据，我们的下一个目标是扩展 对更复杂的CM患者的内源性µ-阿片类神经传递的投资和调节。 我们将研究这种μ阿片功能障碍如何影响其他关键的中央神经递质（D2/D3 多巴胺）和系统（感官和奖励），导致担心痛苦/情感痛苦。 内源性μ-阿片类和D2/D3多巴胺可以说是最关键的两种分子机制 负责疼痛和情绪调节；它们是最有效行动的主要目标 外源性镇痛药和精神病药物可用。我们最初使用[11C] Carfentanil的PET的EM研究， 选择性μ阿片类接收器（μOR）radiotracer显示出μor的可用性降低（非 - 在攻击过程中，EM患者的大脑中可取代的结合电位[BPND]）。值得注意的是，我们的初步 数据表明，随着到CM的进展，μ-阿片类（肽）释放进一步增加 杏仁核与攻击严重程度和异常性相关。 EM攻击也伴随着 通过[11C] raclopride在基底神经节中测量的Da D2/D3 BPND的增加，并且 攻击的历史和复发，较低的发作性内源性DA释放较低。我们是第一个 证明针对主要运动皮层（M1）的非侵入性神经调节方法， 经颅直流刺激（TDC）可以立即调节µOR系统。我们进一步 开发了M1高清TDCS单曲（M11 HD-TDCS），该单位显着逆转了μorbpnd EM患者更常见和CM特异性临床终点（例如，每天中度/重度 月）。基于我们先前在EM中的R01的坚实和有说服力的数据，我们的续签项目扩展了 通过直接评估和调节关键的神经递质，与系统/症状相关的相关性 疼痛最有弹性的偏头痛，CM：AIM1。用宠物证明患者 在内源性μ阿片类和D2/D3多巴胺中，CM的进展比EM表现出更高的功能障碍 神经传递与它们的攻击频率和剧烈疼痛相关； AIM2。评价 商业对神经元系统连通性的影响和大胆的信号变异性及其关联 神经传递的功能障碍和攻击的担忧； AIM3。调查是否每天20 基于实验室/家庭的单侧和双侧M11-2 HD-TDCS调制对分子的影响不同， CM患者的系统和临床状态。