Neurobiology and Treatment of Pain

描述（由申请人提供）：这是一项新的R 01申请，为响应RFA-DA-09-017而提交，旨在研究大鼠中疼痛的神经生物学、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效应之间的相互作用。疼痛是一个重要的公共卫生问题，阿片类镇痛药是治疗疼痛的主要药物。然而，现有阿片类药物的使用受到副作用的限制，包括高滥用风险，开发降低滥用风险的强效镇痛剂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。本申请基于以下前提：（1）疼痛的主要和临床显著体征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（即情感镇痛）。在这个应用中，我们建议使用大鼠颅内自我刺激（ICSS）测定来建立疼痛诱导的行为抑郁和情感镇痛模型。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制，我们认为ICSS也将作为神经生物学研究和疼痛情感成分治疗的工具。为了支持这一说法，我们提供了初步数据，表明大鼠ICSS被常用的伤害性刺激（IP注射稀酸）抑制，并且疼痛诱导的ICSS抑制被镇痛阿片类吗啡阻断，但被阿片受体激动剂U69，593加重。提出了四个具体目标，以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工具，系统评价阿片和单胺神经递质系统在疼痛抑制ICSS和情感镇痛中的作用。我们假设阿片和单胺能系统在疼痛诱导的抑郁和情感镇痛的表达中起关键作用。具体目标2将评估先前单独暴露于吗啡、单独暴露于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促进作用的影响。我们假设，先前暴露于阿片类镇痛将不太可能比先前暴露于阿片类药物单独提高随后的阿片类药物促进ICSS。具体目标3将检查慢性炎性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，吗啡会产生更大的促进ICSS从慢性疼痛基线抑郁ICSS比从非疼痛或疼痛后ICSS基线。具体目标4将检验以下假设：ICSS的疼痛相关抑郁与丘脑核中CREB-强啡肽通路的激活相关。我们预测疼痛会刺激伏隔核中CREB磷酸化和强啡肽合成，并且这些疼痛效应会被情感镇痛药阻断。 公共卫生相关性：疼痛和药物滥用都是重要的公共卫生问题，疼痛和药物滥用的机制可能重叠和相互作用。这个应用程序是建立在这样的假设，即专注于疼痛的情感成分可能会提供一个特别有用的框架的行为数据，以指导疼痛和药物滥用机制之间的相互作用的补充研究。研究建议：（1）在通常用于模拟大鼠动机和影响的行为测定中检查疼痛和镇痛药物之间的行为相互作用，以及（2）评估这些相互作用在大脑主要奖励途径中的神经化学相关性。

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.