Neurobiology and Treatment of Pain

神经生物学和疼痛治疗

• 批准号: 8317661
• 负责人: Sidney S Negus
• 金额: $ 32.41万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317661
• 关键词: Absence of pain sensation; Absenteeism at work; Acids; Acute; Address; Adverse effects; Affect; Affective; Agonist; Analgesics; Animals; Area; Behavior; Behavioral; Behavioral Assay; Behavioral Medicine; Biological Assay; Brain; CREB1 gene; Chemicals; Chronic; Clinical Medicine; Coupled; Data; Depressed mood; Drug Addiction; Drug abuse; Drug usage; Dynorphins; Evaluation; Exposure to; Gene Activation; Genetic Transcription; Goals; Grooming; Human; Incidence; Individual; Inflammatory; Intraperitoneal Injections; Lactic acid; Lead; Locomotion; Mental Depression; Modeling; Monitor; Moods; Morphine; Motivation; Motor; Neurobiology; Neuropathy; Neuropharmacology; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Opioid; Opioid Analgesics; Pain; Pain management; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Procedures; Public Health; Quality of life; Rattus; Research; Rewards; Role; Self Stimulation; Serotonin Uptake Inhibitors; Social Interaction; Societies; Stimulus; System; Testing; Veterinary Medicine; addiction; chronic pain; clinically significant; dopamine system; drug development; drug reward; feeding; improved; inflammatory neuropathic pain; meetings; monoamine; motivated behavior; neurochemistry; novel; preclinical study; response; restoration; success; tool

This is a new R01 application, submitted in response to RFA-DA-09-017, to study the neurobiology of pain, the neuropharmacology of analgesia, and the interactions between analgesic and abuse-related effects of opioids and other drugs in rats. Pain is a significant public health problem, and opioid analgesics constitute a principal class of drugs used to treat pain. However, the use of existing opioids is limited by side effects that include high abuse liability, and efforts to develop strong analgesics with reduced abuse liability have met with limited success. We and others have argued that improved progress in pain management and analgesic drug development may benefit from research on the neurobiology and neuropharmacology of the affective components of pain. This application is founded on the premises that (1) a cardinal and clinically significant sign of pain is depression of both behavior and mood, and (2) a key goal in pain treatment is a restoration of pain-depressed behaviors and an improvement in pain-depressed mood (i.e. affective analgesia). In this application, we propose to model pain-induced behavioral depression and affective analgesia using an assay of intracranial self-stimulation (ICSS) in rats. This procedure has been widely used to study modulation of motivated behavior and affect by drugs and other manipulations, and we submit that ICSS will also be useful as a tool for research on the neurobiology and treatment of affective components of pain. In support of this claim, we provide preliminary data to show that ICSS in rats is depressed by a commonly used noxious stimulus (IP injection of dilute acid), and that pain-induced depression of ICSS is blocked by the analgesic opioid morphine but exacerbated by the prodepressant kappa opioid agonist U69,593. Four specific aims are proposed to extend these initial findings. Specific Aim 1 will use systemically administered pharmacologic tools in a systematic evaluation of the role of opioid and monoamine neurotransmitter systems in pain- depressed ICSS and affective analgesia. We hypothesize a key role for opioid and monoaminergic systems in expression of pain-induced depression and affective analgesia. Specific Aim 2 will evaluate effects of previous exposure to morphine alone, noxious stimuli alone, or noxious stimuli+opioid (i.e. analgesia) on opioid-induced facilitation of ICSS. We hypothesize that prior exposure to opioid analgesia will be less likely than prior exposure to opioid alone to enhance subsequent opioid facilitation of ICSS. Specific Aim 3 will examine effects of chronic inflammatory and neuropathic pain manipulations on ICSS. We hypothesize that chronic pain will depress ICSS, and that morphine will produce greater facilitation of ICSS from a chronic-pain baseline of depressed ICSS than from non-pain or post-pain ICSS baselines. Specific Aim 4 will test the hypothesis that pain-related depression of ICSS correlates with activation of the prodepressant CREB- Dynorphin pathway in nucleus accumbens. We predict that pain will stimulate CREB phosphorylation and dynorphin synthesis in nucleus accumbens, and that these pain effects will be blocked by affective analgesics.

这是一项新的R 01申请，提交以响应RFA-DA-09-017，研究疼痛的神经生物学， 镇痛的神经药理学，以及阿片类药物的镇痛和滥用相关作用之间的相互作用 和其他药物。疼痛是一个重要的公共卫生问题，阿片类镇痛药是主要的 用于治疗疼痛的一类药物。然而，现有阿片类药物的使用受到副作用的限制，包括 滥用可能性高，开发强效镇痛药以减少滥用可能性的努力受到限制 成功我们和其他人认为，疼痛管理和镇痛药物的进步 发展可能受益于情感的神经生物学和神经药理学的研究， 疼痛的组成部分。本申请基于以下前提：（1）一个基本的和临床上重要的 疼痛的标志是行为和情绪的抑郁，以及（2）疼痛治疗的关键目标是恢复 疼痛-抑郁行为和疼痛-抑郁情绪的改善（即情感镇痛）。在这 应用，我们建议使用一种测定方法来模拟疼痛诱导的行为抑郁和情感镇痛 颅内自我刺激（ICSS）。这一过程已被广泛用于研究调制 动机行为和药物和其他操作的影响，我们认为ICSS也将是有用的 作为研究神经生物学和治疗疼痛情感成分的工具。为支持这一 声称，我们提供的初步数据表明，大鼠ICSS是由一种常用的有毒物质， 刺激（IP注射稀酸），且疼痛诱导ICSS抑制被镇痛剂阻断 阿片类吗啡，但由前阿片受体激动剂U69，593加重。四个具体目标是 建议扩大这些初步调查结果。具体目标1将使用全身给药的药理学 系统评价阿片类和单胺神经递质系统在疼痛中的作用的工具- 抑制ICSS和情感镇痛。我们假设阿片和单胺能系统在 表达疼痛诱发的抑郁和情感镇痛。具体目标2将评估 先前暴露于单独的吗啡、单独的伤害性刺激或伤害性刺激+阿片类药物（即镇痛） 阿片类药物诱导的ICSS易化。我们假设，先前暴露于阿片类镇痛药将不太可能 与先前单独暴露于阿片样物质相比，可增强随后的阿片样物质对ICSS的促进作用。第3章将 检查慢性炎症和神经性疼痛操作对ICSS的影响。我们假设 慢性疼痛会抑制ICSS，而吗啡会对慢性疼痛的ICSS产生更大的促进作用。 与无疼痛或疼痛后ICSS基线相比，抑郁ICSS基线。第4章测试 ICSS疼痛相关性抑郁与CREB-1蛋白激活相关的假说 延髓核强啡肽通路。我们预测疼痛会刺激CREB磷酸化， 强啡肽的合成，并且这些疼痛效应将被情感性镇痛剂阻断。