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

摘要 发作性偏头痛(EM)患者可发展为疾病的进展性状态，超过15 每月的攻击次数。这种状态被称为慢性偏头痛(CM)，一种严重影响 患者的日常生活中有更频繁的感觉和情感痛苦以及可能的药物滥用， 尤其是鸦片类药物。基于我们最初关于EM的R01的严格科学数据，我们的下一个目标是扩大 复杂心肌梗塞患者内源性阿片类神经递质的研究及调控。 我们将研究这种µ-阿片类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/情感痛苦的恶化。这个 内源性μ阿片和D2/D3多巴胺是两个最关键的分子机制 负责疼痛和情绪调节；他们是最有力的行动的首要目标 可提供外源性止痛药和精神病药。我们最初的EM研究使用PET和[11C]卡芬太尼， 一种选择性μ阿片受体(μOR)放射性示踪剂，已显示μOR可用性(非 EM患者发作时脑组织中的可置换结合电位[BPND]。值得注意的是，我们的初步调查 数据显示，随着进展到CM，μ-阿片(肽)的释放在 杏仁核与发作严重程度和痛觉过敏有关。EM袭击还伴随着 [11C]raclopride测量的DA D2/D3 BPND在基底节的增加，且时间越长 发作病史和复发次数越少，发作期内源性DA释放越低。我们是第一个 证明了一种针对初级运动皮质(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高清晰度TDCSMOTGE(M11 HD-TDCS)，显著逆转了μ或BPND 更频繁的EM患者和更少的特定于CM的临床终点(例如， 月)。基于我们之前在EM的R01中可靠且有说服力的数据，我们的续订项目扩展了其 通过直接评估和调节关键神经递质、相关系统/症状的相关性 偏头痛最具弹性的疼痛，CM：AIM1。使用正电子发射计算机断层扫描技术证明 在内源性μ阿片和D2/D3多巴胺方面，CM比EM表现出更高的功能障碍 神经传递与其发作频率和剧烈疼痛痛苦相关；评估 CM对神经元系统连通性和BOLD信号变异性的影响及其联系 神经传递功能障碍，发作加重；调查每天是否有20人 基于实验室/家庭的单侧和双侧M11-2 HD-tDCS调制对分子有不同的影响， CM患者的系统和临床状态。

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.