Neurobiology and Treatment of Pain
神经生物学和疼痛治疗
基本信息
- 批准号:7763513
- 负责人:
- 金额:$ 33.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Absence of pain sensationAbsenteeism at workAcidsAcuteAddressAdverse effectsAffectAffectiveAgonistAnalgesicsAnimalsAreaBehaviorBehavioralBehavioral AssayBehavioral MedicineBiological AssayBrainCREB1 geneChemicalsChronicClassificationClinical MedicineCoupledDataDepressed moodDrug AddictionDrug abuseDrug usageDynorphinsEvaluationExposure toGene ActivationGenetic TranscriptionGoalsGroomingHumanIncidenceIndividualInflammatoryIntraperitoneal InjectionsLactic acidLeadLocomotionModelingMonitorMoodsMorphineMotivationMotorNeurobiologyNeuropathyNeuropharmacologyNeurotransmittersNorepinephrineNucleus AccumbensOpioidOpioid AnalgesicsPainPain managementPathway interactionsPharmaceutical PreparationsPhosphorylationProceduresPublic HealthQuality of lifeRattusResearchRewardsRoleSelf StimulationSerotonin Uptake InhibitorsSocial InteractionSocietiesStimulusSystemTestingVeterinary Medicineaddictionchronic painclinically significantdepresseddepressiondopamine systemdrug developmentdrug rewardfeedingimprovedinflammatory neuropathic painmeetingsmonoaminemotivated behaviorneurochemistrynovelpreclinical studypublic health relevanceresponserestorationsuccesstool
项目摘要
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):这是一项新的 R01 申请,针对 RFA-DA-09-017 提交,旨在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和滥用相关作用之间的相互作用和其他药物在大鼠中的作用。疼痛是一个重要的公共卫生问题,阿片类镇痛药是用于治疗疼痛的主要一类药物。然而,现有阿片类药物的使用受到包括高滥用倾向在内的副作用的限制,并且开发具有降低滥用倾向的强效镇痛药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对疼痛情感成分的神经生物学和神经药理学的研究。该申请基于以下前提:(1) 疼痛的主要且具有临床意义的体征是行为和情绪的抑制,以及 (2) 疼痛治疗的关键目标是恢复疼痛抑制的行为和改善疼痛-情绪低落(即情感性镇痛)。在此应用中,我们建议使用大鼠颅内自刺激(ICSS)测定来模拟疼痛引起的行为抑郁和情感镇痛。该程序已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 也可用作神经生物学研究和疼痛情感成分治疗的工具。为了支持这一主张,我们提供了初步数据,表明大鼠的 ICSS 会因常用的有害刺激(腹腔注射稀酸)而受到抑制,而疼痛引起的 ICSS 抑制会被镇痛阿片类吗啡所阻断,但会因阿片类药物吗啡而加剧。促抑郁剂 kappa 阿片类激动剂 U69,593。提出了四个具体目标来扩展这些初步发现。具体目标 1 将使用系统管理的药理学工具系统评估阿片类药物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发挥关键作用。具体目标 2 将评估先前单独接触吗啡、单独接触有害刺激或有害刺激+阿片类药物(即镇痛)对阿片类药物诱导的 ICSS 促进的影响。我们假设,与先前单独使用阿片类药物相比,先前使用阿片类药物镇痛不太可能增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,并且与非疼痛或疼痛后 ICSS 基线相比,吗啡会从抑制 ICSS 的慢性疼痛基线产生更大的 ICSS 促进作用。具体目标 4 将检验以下假设:ICSS 的疼痛相关抑郁症与伏隔核中促抑郁剂 CREB-强啡肽通路的激活相关。我们预测疼痛会刺激伏隔核中的 CREB 磷酸化和强啡肽合成,并且这些疼痛效应将被情感镇痛药阻断。
公共卫生相关性:疼痛和药物滥用都是重大的公共卫生问题,疼痛和药物滥用的潜在机制可能重叠和相互作用。该应用程序基于这样的假设:对疼痛的情感成分的关注可能会提供一个特别有用的行为数据框架,以指导对疼痛和药物滥用机制之间相互作用的补充研究。拟议的研究目的是(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)评估大脑主要奖励途径中这些相互作用的神经化学相关性。
项目成果
期刊论文数量(0)
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Sidney S Negus其他文献
Sidney S Negus的其他文献
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{{ truncateString('Sidney S Negus', 18)}}的其他基金
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Endocannabinoid modulation of pain-depressed behavior
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- 批准号:
8462583 - 财政年份:2011
- 资助金额:
$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
内源性大麻素对疼痛抑制行为的调节
- 批准号:
9403737 - 财政年份:2011
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$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
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- 批准号:
8851547 - 财政年份:2011
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$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
内源性大麻素对疼痛抑制行为的调节
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8287528 - 财政年份:2011
- 资助金额:
$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
内源性大麻素对疼痛抑制行为的调节
- 批准号:
8115635 - 财政年份:2011
- 资助金额:
$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
内源性大麻素对疼痛抑制行为的调节
- 批准号:
9403737 - 财政年份:2011
- 资助金额:
$ 33.45万 - 项目类别:
Endocannabinoid modulation of pain-depressed behavior
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8653551 - 财政年份:2011
- 资助金额:
$ 33.45万 - 项目类别:
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