Neurobiology and Treatment of Pain

神经生物学和疼痛治疗

• 批准号: 8317661
• 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/8317661
• 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; response; restoration; success; tool

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.

这是一项新的R01申请，是根据RFA-DA-09-017提交的，用于研究疼痛的神经生物学