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（由申请人提供）：这是一种新的R01应用程序，响应于RFA-DA-09-017，用于研究疼痛的神经生物学，镇痛神经药理学以及阿片类药物与大鼠的其他药物的镇痛和虐待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，阿片类镇痛药构成用于治疗疼痛的主要药物类别。但是，现有阿片类药物的使用受到包括高虐待责任的副作用的限制，并且努力发展出强大的镇痛学责任降低的责任已达到有限的成功。我们和其他人认为，疼痛管理和镇痛药发育的进展改善可能会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。该应用建立在以下前提下：（1）基本和临床上显着的疼痛迹象是行为和情绪的抑郁，（2）疼痛治疗的关键目标是恢复疼痛抑郁的行为和疼痛抑郁的情绪改善（即情感镇痛）。在此应用中，我们建议使用大鼠中颅内自刺激（ICS）的测定法对疼痛引起的行为抑郁和情感镇痛进行建模。该程序已被广泛用于研究动机行为的调节和受到药物和其他操纵的影响，我们认为ICS也将是研究神经生物学和治疗疼痛情感成分的工具。为了支持这一说法，我们提供了初步数据，以表明大鼠的ICS被常用的有害刺激（IP注入稀酸IP注入）抑制，并且ICS疼痛诱导的ICS抑郁症被镇痛药阿片类吗啡所阻断，但会受到proade剂Kappa apepressant kappa apepressant kappa apopioid apioid agonist agonist agonist agonist U69,59,59,59,593。提出了四个具体目标来扩展这些初始发现。具体目标1将在系统评估阿片类药物和单胺神经递质系统在疼痛抑郁的ICS和情感镇痛中的作用中进行系统评估。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中起关键作用。具体目标2将评估单独接触吗啡，单独的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ICS促进的影响。我们假设事先暴露于阿片类镇痛的可能性要比单独接触阿片类药物的可能性较小，以增强随后的阿片类药物促进性ICS。具体目标3将检查慢性炎症和神经性疼痛操纵对ICS的影响。我们假设慢性疼痛会抑制ICS，并且吗啡将从抑郁的ICS的慢性抑制基线基线比非苦难或后皮林ICSS碱基产生更大的ICS促进。具体目标4将检验以下假设：ICS与疼痛相关的抑郁与伏隔核中抑郁症的CREB-强啡肽途径的激活相关。我们预测疼痛会刺激伏隔核中的CREB磷酸化和驱虫素的合成，并且这些疼痛作用将被情感镇痛药阻止。 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，疼痛和药物滥用的机制可能重叠和相互作用。该应用是基于以下假设：对疼痛的情感组成部分的关注可能会提供一个特别有用的行为数据框架，以指导互补研究疼痛和药物滥用机制之间的相互作用。提出研究以（1）检查疼痛和镇痛药之间的行为相互作用，通常用于模拟大鼠的动机和影响的行为测定中，以及（2）评估这些相互作用在大脑主奖励途径中的神经化学相关性。