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

椎上阿片电路在前额 TMS 诱导镇痛中的作用

基本信息

批准号：
8452350
负责人：
Joseph Jeffrey Taylor
金额：
$ 4.32万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-22 至 2015-03-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452350
关键词：
Absence of pain sensation Accident and Emergency department Address Adverse effects Analgesics Basic Science Binding Brain Capsaicin Chemicals Clinic Clinical Cognition Conflict (Psychology)Coupling Cross-Over Studies Data Diffusion Magnetic Resonance Imaging Dose Dose-Limiting Double-Blind Method Evaluation Frequencies Functional Magnetic Resonance Imaging Goals Health Human Intravenous Intravenous infusion procedures Laboratories Laboratory Animals Laboratory Study Lead Left Link Magnetic Resonance Imaging Measures Mediating Methods Modeling Mood Disorders Morbidity - disease rate Morphine Naloxone Narcotic Analgesics National Institute of Neurological Disorders and Stroke Neuropharmacology Nociception Opiates Opioid Opioid Analgesics Overdose Pain Pain Threshold Pain management Panic Disorder Participant Patients Perception Pharmaceutical Preparations Physiological Physiology Postoperative Pain Postoperative Period Prefrontal Cortex Prevalence Recruitment Activity Reporting Research Design Risk Rodent Role Saline Self Administration Self-Administered Sensory Severities Signal Transduction Skin Testing Time Transcranial magnetic stimulation Translational Research Visit bariatric surgery blood oxygen level dependent chronic pain clinically relevant endogenous opioids experience immunoreactivity midbrain central gray substance mortality neuropsychiatry nonmedical use opioid abuse prescription opiate repetitive transcranial magnetic stimulation therapy development tool trend

项目摘要

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.

描述（由申请人提供）：用于疼痛管理的阿片类镇痛药在滥用潜力和剂量依赖性副作用方面构成重大健康风险。在过去十年中，因非医疗使用这些药物而导致的急诊室就诊和致命中毒分别增加了一倍和三倍多。尽管存在这些令人担忧的趋势，但由于慢性疼痛的普遍性和严重性，阿片类药物的处方量仍在继续增加。降低阿片类药物相关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辅助疗法。研究表明，rTMS 可以减轻实验诱发的疼痛和慢性疼痛。在一项研究中，术后左背外侧前额皮质 (DLPFC) rTMS 的单次疗程可将吗啡自我给药量减少 40%。在 DLPFC rTMS 被评估为疼痛的辅助疗法之前，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 通过脊髓上阿片电路 (SOC) 的增益调节介导自上而下的镇痛，包括导水管周围灰质 (PAG) 和延髓前腹内侧 (RVM)。本研究的目的是检查 DLPFC rTMS 是否通过激活 SOC 来诱导镇痛。假设：左 DLPFC rTMS 将诱导纳洛酮可逆性疼痛耐受性增加，这与纳洛酮可逆性 PAG-RVM BOLD 信号增加相关。具体目标： (1) 描述 DLPFC rTMS 诱导镇痛的时间过程和强度。 (2)确定左DLPFC rTMS诱导的镇痛是否对μ阿片类药物阻断敏感。 (3) 识别左 DLFPC rTMS 诱导镇痛的大脑回路，并检查该回路中的有效连接。方法：目标 1 和 2 将通过双假对照、双盲、交叉研究来实现。在第一次实验访问中，参与者将在真正或假的左 DLPFC rTMS 之前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，但接受相反的静脉输注。热电极将用于通过对未处理的皮肤进行定量感官测试以及在 TMS 治疗之前和之后 0、20 和 40 分钟对经过辣椒素处理的皮肤进行块测试来评估疼痛感知。目标 3 将在 3T MRI 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辅助疗法。这项研究使用 rTMS 作为介入工具来研究疼痛回路，同时评估其作为疼痛辅助疗法的潜力。