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.

这是一个新的R01应用程序，响应RFA-DA-09-017，以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与滥用相关的作用之间的相互作用 和其他大鼠的药物。疼痛是一个重大的公共卫生问题，阿片类镇痛药构成校长 用于治疗疼痛的药物类别。但是，现有阿片类药物的使用受到副作用的限制，包括 高度虐待责任，以及以减少的虐待责任促进强大的镇痛药的努力有限 成功。我们和其他人认为，疼痛管理和镇痛药的进展有所改善 发展可能会受益于有关情感的神经生物学和神经药理的研究 疼痛的成分。该申请建立在（1）基本和临床意义的前提下 疼痛的迹象是行为和情绪的抑郁症，（2）疼痛治疗的关键目标是恢复 止痛的行为和疼痛抑郁的情绪改善（即情感镇痛）。在这个 应用，我们建议使用测定法对疼痛引起的行为抑郁和情感镇痛进行建模 大鼠颅内自刺激（ICS）。此过程已被广泛用于研究 动机行为和受到毒品和其他操纵的影响，我们认为ICS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。支持这个 主张，我们提供初步数据，以表明大鼠中的ICS被常用的有害性抑制 刺激（注射稀酸的IP），并且疼痛诱导的ICS抑郁被镇痛阻塞 阿片类吗啡，但被抑制剂kappa阿片类药物A激动剂U69,593加剧。四个具体目标是 提议扩展这些初始发现。特定目标1将使用系统管理的药理学 在系统评估阿片类药物和单胺神经递质系统在疼痛中的作用的工具 - 抑郁的ICS和情感镇痛。我们假设阿片类药物和单胺能系统在 疼痛引起的抑郁和情感镇痛的表达。具体目标2将评估 先前仅暴露于吗啡，单独暴露于吗啡，单独刺激或有害刺激+阿片类药物（即镇痛） 阿片类药物引起的ICS促进。我们假设事先接触阿片类镇痛的可能性较小 比仅先前接触阿片类药物，以增强ICS的随后的阿片类药物促进。具体的目标3将 检查慢性炎症和神经性疼痛操纵对ICS的影响。我们假设这一点 慢性疼痛会抑制ICS，并且吗啡将产生更大的促进性ICS 抑郁型ICS的基线比非苦苦或后ICSS基线的基线。特定目标4将测试 ICS疼痛相关抑郁的假设与激活的抑郁症相关 伏隔核中的驱肽途径。我们预测疼痛会刺激CREB磷酸化和 伏隔核中的巨啡合成，这些疼痛作用将被情感镇痛药阻止。