Neurobiology and Treatment of Pain

这是响应RFA-DA-09-017提交的新的R01申请，用于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剂和滥用相关效应之间的相互作用 和其他药物在老鼠身上。疼痛是一个重大的公共卫生问题，阿片类镇痛剂是主要的 用于治疗疼痛的药物类别。然而，现有阿片类药物的使用受到副作用的限制，包括 滥用责任高，努力开发强效止痛药，减少滥用责任，但遇到的困难有限 成功。我们和其他人认为，疼痛管理和止痛药方面的进步 情感性精神障碍的神经生物学和神经药理学研究可能对发展有所裨益 疼痛的组成部分。本申请是建立在以下前提之上的：(1)具有重要临床意义的 疼痛的迹象是行为和情绪的抑郁，以及(2)疼痛治疗的一个关键目标是恢复 疼痛抑制行为和疼痛抑制情绪的改善(即情感止痛)。在这 应用，我们建议使用一种方法来模拟疼痛诱导的行为抑郁和情感止痛 大鼠的颅内自我刺激(ICSS)。这一过程已被广泛用于研究光信号的调制 受药物和其他操纵的激励行为和影响，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。为了支持这一点 声称，我们提供的初步数据表明，大鼠的ICSS受到一种常用的有毒物质的抑制 刺激(ip注射稀酸)，痛性抑制ICSS可被止痛剂阻断 阿片类吗啡，但被促抑郁剂kappa阿片激动剂U69,593加重。四个具体目标是 提议延长这些初步调查结果。特定目标1将使用系统管理的药剂 系统评估阿片类和单胺类神经递质系统在疼痛中的作用的工具- 抑制ICSS与情感镇痛。我们假设阿片类药物和单胺能系统在 痛性抑郁的表达与情感镇痛。具体目标2将评估以下方面的效果 既往单独接触吗啡、单独接触有害刺激或有害刺激阿片类药物(即止痛) 阿片类药物诱导的ICSS易化。我们假设先前接触阿片类止痛药的可能性较小。 而不是事先单独接触阿片类药物，以加强随后的阿片类药物对ICSS的促进作用。具体目标3将 检查慢性炎症性和神经病理性疼痛手法对ICSS的影响。我们假设 慢性疼痛会抑制ICSS，而吗啡会从慢性疼痛中更好地促进ICSS 抑郁的ICSS的基线比无疼痛或疼痛后的ICSS基线要好。《特定目标4》将测试 假设ICSS的疼痛相关抑郁与促抑郁药CREB的激活相关- 伏隔核中的强啡肽通路。我们预测疼痛会刺激CREB的磷酸化，并 伏隔核中强啡肽的合成，这些疼痛效应将被情感性镇痛剂阻断。

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.