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

描述(由申请人提供)：阿片类止痛药用于疼痛治疗，在滥用潜力和剂量依赖的副作用方面构成重大的健康风险。在过去十年里，急诊室就诊和非医疗使用这些药物导致的致命中毒分别增加了一倍多和两倍以上。尽管有这些令人震惊的趋势，但由于慢性疼痛的流行和严重程度，阿片类药物的处方继续增加。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止痛所必需的阿片类药物剂量的疗法。一种被称为重复经颅磁刺激(RTMS)的局部、非侵入性脑刺激形式已经成为一种潜在的疼痛控制辅助疗法。研究表明，rTMS可以减少实验性疼痛和慢性疼痛。在一项研究中，术后单次左侧背外侧前额叶皮质(DLPFC)rTMS可使吗啡自我注射减少40%。在DLPFC rTMS被评估为疼痛的辅助治疗之前，需要研究揭示它是如何改变神经药理学和大脑活动的。有许多间接证据表明，DLPFC通过调节脊髓上阿片能环路(SOC)，包括导水管周围灰质(PAG)和延髓轮状腹内侧部(RVM)，介导自上而下的镇痛。本研究的目的是探讨DLPFC rTMS是否通过激活SOC而产生镇痛作用。假设：左侧DLPFC rTMS将诱导纳洛酮可逆的疼痛耐受性增加，这与PAG-RVM BOLD信号的纳洛酮可逆性增加相关。具体目的：(1)描述DLPFC rTMS诱导的镇痛的时程和幅度。(2)确定左侧DLPFC rTMS的镇痛作用是否对Mu阿片类药物敏感。(3)确定左侧DLFPC rTMS镇痛背后的脑环路，并检测该环路的有效连接。方法：目标1和目标2将通过双假对照、双盲、交叉研究来实现。在第一次实验性访问中，参与者将在真正的或假的左侧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，但相反的静脉输液。在TMS治疗前和治疗后0、20和40分钟，将使用温度模式通过对未经处理的皮肤进行定量感觉测试和对经过辣椒素处理的皮肤进行块测试来评估痛觉。Aim 3将在3T磁共振扫描仪内使用类似的研究设计来实现。交错TMS-fMRI将用于测量DLPFC rTMS引起的血氧水平依赖(BOLD)信号的变化。将使用动态因果建模(DCM)分析来检查DLPFC和PAG-RVM之间的有效连接。与NINDS相关：与麻醉性止痛药相关的发病率和死亡率数据表明，迫切需要找到治疗慢性和术后疼痛的辅助疗法。这项研究使用rTMS作为一种介入工具来研究疼痛回路，同时评估其作为疼痛辅助治疗的潜力。 与公共卫生相关：尽管阿片类药物滥用的增加令人震惊，但由于慢性疼痛的流行和严重程度，麻醉性止痛药的处方继续增加。经颅磁刺激(TMS)是一种非侵入性的脑刺激形式，在实验室和临床上已被证明可以减轻疼痛。本研究的目的是确定TMS缓解疼痛的机制，以便它可以用于减少阿片类药物在慢性和术后疼痛治疗中的作用。

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. PUBLIC HEALTH RELEVANCE: Despite an alarming rise in opiate abuse, prescriptions for narcotic analgesics continue to rise because of the prevalence and severity of chronic pain. Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that has been shown to reduce pain in the laboratory and the clinic. The purpose of this study is to determine the mechanism by which TMS relieves pain so that it can be used to reduce the role of opiates in chronic and postoperative pain management.