Neurobiology and Treatment of Pain

神经生物学和疼痛治疗

• 批准号: 8117119
• 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/8117119
• 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; public health relevance; response; restoration; success; tool

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.

描述(申请人提供)：这是一个新的R01申请，响应RFA-DA-09-017，研究疼痛的神经生物学，止痛的神经药理学，以及阿片类药物和其他药物的止痛剂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，阿片类止痛药是用于治疗疼痛的主要药物类别。然而，现有阿片类药物的使用受到包括高滥用责任在内的副作用的限制，开发具有减少滥用责任的强效镇痛剂的努力取得的成功有限。我们和其他人认为，疼痛管理和止痛药开发方面的进步可能受益于对疼痛情感成分的神经生物学和神经药理学的研究。这一应用的前提是：(1)疼痛的一个基本的和临床上有意义的迹象是行为和情绪的抑郁，(2)疼痛治疗的一个关键目标是恢复疼痛抑郁的行为和改善疼痛抑郁的情绪(即情感止痛)。在这一应用中，我们建议使用大鼠颅内自我刺激(ICSS)的方法来建立疼痛诱导的行为抑郁和情感镇痛的模型。这一过程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也将作为神经生物学研究和疼痛情感成分治疗的有用工具。为了支持这一说法，我们提供了初步的数据，表明大鼠的ICSS受到常用的伤害性刺激(IP注射稀酸)的抑制，疼痛诱导的ICSS抑制可被止痛剂阿片类吗啡阻断，但可被促抑郁剂kappa阿片激动剂U69,593加剧。提出了四个具体目标来扩大这些初步调查结果。具体目标1将使用系统管理的药理学工具，系统地评估阿片类神经递质和单胺类神经递质系统在抑制疼痛的ICSS和情感止痛中的作用。我们假设阿片和单胺能系统在表达疼痛诱导的抑郁和情感镇痛中起关键作用。具体目标2将评估既往单独接触吗啡、单独使用伤害性刺激或伤害性刺激+阿片类药物(即镇痛)对阿片类药物诱导的ICSS易化的影响。我们假设，先前使用阿片类止痛药的可能性低于先前单独使用阿片类药物的可能性，以增强ICSS随后的阿片类药物易化作用。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。我们假设慢性疼痛将抑制ICSS，并且吗啡将从抑郁的ICSS的慢性疼痛基线比无疼痛或疼痛后的ICSS基线产生更大的ICSS促进作用。具体目标4将验证这一假说，即ICSS的疼痛相关抑制与伏隔核中促抑郁剂CREB-强啡肽通路的激活有关。我们预测疼痛将刺激伏隔核内CREB的磷酸化和强啡肽的合成，而这些疼痛效应将被情感性镇痛剂所阻断。 公共卫生相关性：疼痛和药物滥用都是重大的公共卫生问题，导致疼痛和药物滥用的机制可能重叠和相互作用。这一应用建立在这样的假设基础上，即对疼痛的情感成分的关注可能提供一个特别有用的行为数据框架，以指导关于疼痛和药物滥用机制之间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情感的行为测试中检查疼痛和止痛药之间的行为交互作用，以及(2)评估这些交互作用在大脑主要奖励路径中的神经化学相关性。