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.

摘要 发作性偏头痛（EM）患者可以发展为疾病的进行性状态， 每月攻击。这种状态被称为慢性偏头痛（CM），这是一种严重影响患者健康的疾病。 患者的日常生活中更频繁的感觉和情感痛苦以及药物滥用的可能性， 尤其是鸦片制剂。基于我们在EM上的初始R 01的严格科学数据，我们的下一个目标是扩展 研究和调节更复杂CM患者的内源性μ-阿片类神经传递。 我们将研究这种微阿片功能障碍如何影响其他关键的中枢神经递质（D2/D3 多巴胺）和系统（感觉和奖励），导致疼痛/情绪痛苦的恶化。的 内源性μ-阿片和D2/D3多巴胺可以说是两个最关键的分子机制 负责疼痛和情绪调节;他们是最有效的行动的主要目标 外源性止痛药和精神病药物。我们最初的EM研究使用PET与[11 C]卡芬太尼， 一种选择性μ阿片受体（μOR）放射性示踪剂，已证明μOR可用性降低（非 替代结合电位[BPND]）。值得注意的是，我们的初步 数据显示，随着向CM的进展，微囊中μ-阿片样物质（肽）的释放进一步增加， 杏仁核与发作严重程度和异常性疼痛相关。EM袭击还伴随着 基底神经节中[11 C]雷氯必利测量的DA D2/D3 BPND增加，并且 有发作史及复发者，发作期内源性DA释放量较低。我们是第一个 证明了靶向初级运动皮层（M1）的非侵入性神经调节方法， 经颅直流电刺激（tDCS）可以立即调节µOR系统。我们进一步 开发了M1高清tDCS导联（M11 HD-tDCS），在 更频繁的EM患者和减少的CM特异性临床终点（例如，中度/重度天数 月）。我们的更新项目建立在我们之前EM R 01的可靠和有说服力的数据基础上， 通过直接评估和调节关键的神经递质，系统/相关症状 在最有弹性的偏头痛中，CM：Aim 1。用PET证明， CM的进展在内源性μ-阿片样物质和D2/D3多巴胺中显示出比EM更高的功能障碍 神经传递与他们的攻击频率和严重的疼痛痛苦;目标2。评价 CM对神经元系统的连接性和BOLD信号变异性的影响及其关联 伴有神经传递功能障碍和发作恶化; Aim 3.调查是否每天20 基于实验室/家庭的单侧和双侧M11-2 HD-tDCS调节对分子具有不同的影响， 系统和CM患者的临床状态。