Role of the Supraspinal Opioidergic Circuit in Prefrontal TMS-Induced Analgesia

描述（由申请人提供）：用于疼痛管理的阿片类镇痛药在滥用可能性和剂量依赖性副作用方面构成重大健康风险。在过去的十年里，急诊室就诊和非医疗使用这些药物引起的致命中毒分别增加了一倍和两倍多。尽管有这些令人担忧的趋势，但由于慢性疼痛的普遍性和严重性，阿片类药物处方继续增加。降低与阿片类药物相关的风险的一种方法是开发减少实现镇痛所需的阿片类药物剂量的疗法。一种称为重复经颅磁刺激（rTMS）的局部非侵入性脑刺激形式已成为疼痛管理的潜在治疗方法。研究表明，rTMS可以减轻实验诱导的疼痛和慢性疼痛。在一项研究中，术后左背外侧前额叶皮层（DLPFC）rTMS的单次会议减少了40%的吗啡自我给药。在DLPFC rTMS可以作为疼痛的连续治疗进行评估之前，研究需要揭示它如何改变神经药理学和大脑活动。有许多间接证据表明，DLPFC介导的自上而下的镇痛通过增益调制的脊髓上阿片类神经回路（SOC），包括周围导水管灰质（PAG）和延髓头端腹内侧（RVM）。本研究的目的是检查是否DLPFC rTMS诱导镇痛激活SOC. Hypothesis：左DLPFC rTMS将诱导纳洛酮可逆增加疼痛耐受性，与纳洛酮可逆增加PAG-RVM BOLD信号。具体目的：（1）表征DLPFC rTMS诱导镇痛的时间过程和幅度。(2)确定左侧DLPFC rTMS诱导的镇痛是否对μ阿片受体阻滞敏感。(3)识别左侧DLFPC rTMS诱导镇痛的脑回路，并检查该回路的有效连接。方法：目标1和2将通过双假对照、双盲、交叉研究来实现。在第一次实验访视时，受试者将在真实的或假左侧DLPFC rTMS之前立即随机接受静脉注射生理盐水或纳洛酮。一周后，参与者将接受相同的TMS治疗，但相反的IV输注。在TMS治疗前和治疗后0、20和40分钟，通过对未治疗皮肤进行定量感觉测试和对辣椒素治疗皮肤进行阻滞测试，使用热电极评估疼痛感知。目标3将在3 T MRI扫描仪内使用类似的研究设计完成。交错TMS-fMRI将用于测量DLPFC rTMS诱导的血氧水平依赖性（BOLD）信号变化。动态因果模型（DCM）分析将用于检查DLPFC和PAG-RVM之间的有效连接。与NINDS的相关性：与麻醉性镇痛药相关的发病率和死亡率数据表明，迫切需要发现慢性疼痛和术后疼痛的预防性治疗方法。本研究使用rTMS作为介入工具来研究疼痛回路，同时评估其作为疼痛持续治疗的潜力。

DESCRIPTION (provided by applicant): Opioid analgesics that are prescribed for pain management pose a significant health risk in terms of abuse potential and dose-dependent side effects. Emergency room visits and fatal poisonings caused by nonmedical use of these medications have more than double and tripled, respectively, within the last decade. Despite these alarming trends, opiate prescriptions continue to rise because of the prevalence and severity of chronic pain. One way to reduce the risks associated with opiates is to develop therapies that reduce the opiate dose necessary to achieve analgesia. A focal, non-invasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential adjunctive therapy for pain management. Studies have shown that rTMS can reduce experimentally induced pain and chronic pain. In one study, a single session of postoperative left dorsolateral prefrontal cortex (DLPFC) rTMS reduced morphine self- administration by 40%. Before DLPFC rTMS can be evaluated as an adjunctive therapy for pain, studies need to reveal how it alters neuropharmacology and brain activity. There are many lines of indirect evidence that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit (SOC), including the periaqueductal gray (PAG) and rostroventromedial medulla (RVM). The purpose of this study is to examine whether DLPFC rTMS induces analgesia by activating the SOC. Hypothesis: Left DLPFC rTMS will induce a naloxone-reversible increase in pain tolerance that correlates with a naloxone-reversible increase in PAG-RVM BOLD signal. Specific Aims: (1) Characterize the time course and magnitude of DLPFC rTMS- induced analgesia. (2) Determine if left DLPFC rTMS-induced analgesia is sensitive to mu opioid blockade. (3) Identify the brain circuitry that underlies left DLFPC rTMS-induced analgesia and examine effective connectivity in that circuit. Methods: Aim 1 and 2 will be accomplished with a double sham-controlled, double- blind, crossover study. On the first experimental visit, participants will randomly receive intravenous saline or naloxone immediately prior to real or sham left DLPFC rTMS. One week later, participants will receive the same TMS treatment but the opposite IV infusion. A thermode will be used to assess pain perception via quantitative sensory testing on untreated skin and block testing on capsaicin-treated skin before and 0, 20 and 40 minutes after TMS treatment. Aim 3 will be accomplished using a similar study design inside of a 3T MRI scanner. Interleaved TMS-fMRI will be used to measure blood oxygen level-dependent (BOLD) signal changes induced by DLPFC rTMS. Dynamic causal modeling (DCM) analysis will be used to examine effective connectivity between DLPFC and PAG-RVM. Relevance to NINDS: Morbidity and mortality data associated with narcotic analgesics demonstrate an urgent need to discover adjunctive therapies for chronic and postoperative pain. This study uses rTMS as an interventional tool to study pain circuitry while simultaneously evaluating its potential as an adjunctive therapy for pain.