Neurobiology and Treatment of Pain

描述（由申请人提供）：这是一个新的R01申请，响应RFA-DA-09-017提交，用于研究大鼠疼痛的神经生物学，镇痛的神经药理学，以及阿片类药物和其他药物的镇痛和滥用相关作用之间的相互作用。疼痛是一个重大的公共卫生问题，阿片类镇痛药是用于治疗疼痛的一类主要药物。然而，现有阿片类药物的使用受到包括高滥用风险在内的副作用的限制，并且开发减少滥用风险的强效镇痛药的努力取得了有限的成功。我们和其他人认为，疼痛管理和镇痛药物开发的进步可能受益于疼痛情感成分的神经生物学和神经药理学研究。这一应用是建立在以下前提之上的：(1)疼痛的主要和临床显著的症状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改善疼痛抑郁情绪（即情感性镇痛）。在这个应用中，我们建议用大鼠颅内自我刺激（ICSS）实验来模拟疼痛诱导的行为抑郁和情感性镇痛。该程序已被广泛用于研究药物和其他操作对动机行为和影响的调节，我们认为ICSS也将有助于研究神经生物学和治疗疼痛的情感成分。为了支持这一说法，我们提供了初步数据，表明大鼠的ICSS被一种常用的有害刺激（稀释酸的IP注射）抑制，疼痛诱导的ICSS抑制被镇痛阿片样物质吗啡阻断，但被促抑郁kappa阿片样物质激动剂U69,593加剧。提出了四个具体目标来扩展这些初步发现。特异性目标1将使用系统给药药理学工具，系统评估阿片类药物和单胺类神经递质系统在疼痛抑制性ICSS和情感性镇痛中的作用。我们假设阿片类药物和单胺能系统在疼痛诱导的抑郁和情感性镇痛的表达中起关键作用。特异性目标2将评估先前单独暴露于吗啡、单独有害刺激或有害刺激+阿片类药物（即镇痛）对阿片类药物诱导的ICSS促进的影响。我们假设先前暴露于阿片类药物镇痛比单独暴露于阿片类药物更不可能增强随后的阿片类药物促进ICSS。特异性目标3将研究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，并且吗啡会在慢性疼痛的ICSS抑郁基线上比在非疼痛或疼痛后ICSS基线上产生更大的ICSS促进作用。特异性目的4将验证ICSS疼痛相关抑郁与伏隔核促抑郁CREB- Dynorphin通路激活相关的假设。我们预测疼痛会刺激伏隔核CREB磷酸化和dynorphin合成，而这些疼痛效应将被情感性镇痛药阻断。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Both pain and drug abuse are significant public health problems, and mechanisms underlying pain and drug abuse may overlap and interact. This application is founded on the hypothesis that a focus on affective components of pain might provide an especially useful framework of behavioral data to guide complementary research on interactions between pain and drug abuse mechanisms. Studies are proposed to (1) examine behavioral interactions between pain and analgesic drugs in a behavioral assay commonly used to model motivation and affect in rats, and (2) assess neurochemical correlates of these interactions in the brain's principal reward pathway.