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
• 负责人: Sidney S Negus
• 金额: $ 31.86万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115635
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Accounting; Adverse effects; Affect; Affective; Agonist; Analgesics; Animals; Appetite Regulation; Area; Autoradiography; Behavior; Behavioral; Binding; Biological Assay; Brain; Brain region; CNS processing; Cancer Patient; Cannabinoids; Characteristics; Clinical; Cognition; Complement; Complex; Data; Depressed mood; Desire for food; Discrimination; Disease; Dissociation; Drug Kinetics; Endocannabinoids; Endogenous depression; Evaluation; Exhibits; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Grooming; Health; Human; Injection of therapeutic agent; Intoxication; Lactic acid; Ligands; Lipids; Locomotion; Marijuana; Marijuana Smoking; Mass Spectrum Analysis; Measures; Membrane; Mental Depression; Metabolic Pathway; Methods; Modeling; Morphine; Motor; Motor Activity; Multiple Sclerosis; Mus; Nature; Nausea and Vomiting; Nucleus Accumbens; Pain; Pain management; Pathology; Patients; Perception; Pharmaceutical Preparations; Pharmacodynamics; Play; Procedures; Process; Property; Protein Binding; Public Health; Relative (related person); Research; Rewards; Role; Schools; Self Stimulation; Signal Pathway; Signal Transduction; Site; Social Interaction; Stimulus; Symptoms; System; Therapeutic; Treatment Efficacy; Treatment outcome; Work; anandamide; base; behavior measurement; clinically significant; drug discrimination; endogenous cannabinoid system; feeding; genetic manipulation; improved; innovation; interest; meetings; motivated behavior; neglect; neurochemistry; new therapeutic target; pre-clinical; pre-clinical research; protein activation; receptor; success

DESCRIPTION (provided by applicant): Pain is a multi-faceted, complex disease that affects all humans. Unfortunately, progress in pain management has been met with limited success. However, considerations of the multiple components of pain have suggested that targeting non-conventional sites could strongly impact the pain management field. The endocannabinoid (eCB) system is one of several lipid signaling systems in the brain and in the body. Verified components of this system include two G-protein coupled receptors, their signaling pathways, two predominant endogenous ligands [anandamide (AEA) and 2-arachidonyl glycerol (2-AG)], and their synthetic and metabolic pathways. The system plays an important modulatory role in many crucial CNS processes (e.g., brain reward, appetite regulation, cognition). Consequently, it is not surprising that this system has been implicated in the pathophysiology of a variety of health problems related to these processes, including pain management. This application is largely based on the idea that a clinically significant component of pain is behavioral depression (i.e., pain-depressed behaviors). In humans, this is indicated by absences from work or school, lack of interest in customary activities, overall decreases in motor activity, and is most often associated with clinical depression. In animals clinical approximation of pain is through decreases in locomotion or grooming and interest in feeding or social interaction. Given these, a promising new strategy for comprehensive treatment of pain is an adjunct focus on pain-depressed behaviors and depressed mood. With this application we plan to evaluate eCB modulation of pain-depressed behaviors using intracranial self-stimulation (ICSS) and drug discrimination (DD) in mice. ICSS has been widely used to study modulation of motivated behavior (i.e. reward) and affect by drugs whereas DD is primarily used to model the subjective/intoxicating effects of drugs. We propose utilizing these well-established operant procedures to evaluate the eCB's effects on pain-induced behavioral depression, affect and intoxication. To complement these behavioral measures, we will determine mechanistic characteristics of affective cannabinoid analgesia versus reward in selected brain regions such as the nucleus accumbens, a brain area implicated in reward and affective pain, through the use of well- established neurochemical analyses such as mass spectrometry and [35S]GTPgS G-protein binding studies. Given the clear need to explore novel therapeutic targets, improve upon existing preclinical pain assays, and incorporate the affective component of pain, we propose that studying the eCB system's modulation of pain-depressed behavior will meet these needs. We feel these studies have significant public health implications and offer a large degree of innovation while relying upon well-established behavioral and neurochemical measures. In summary, considering the paramount public health concern regarding effective pain management this application promises to establish whether the eCB system is a viable and attractive therapeutic means to effectively reduce the great societal burdens associated with pain management. PUBLIC HEALTH RELEVANCE: Pain is a public health concern of utmost importance and is typicaly accompanied by behavioral depression that results in absences from work/school, lack of interest in customary activities, overall decreases in activity, and is most often associated with depresion. Given the clear need to explore novel therapeutic targets, improve upon existing preclinical pain assays, and incorporate the affective component of pain, we propose a thorough evaluation of the endogenous cannabinoid system's ability to ameliorate pain-depressed behavior, while taking into account critical factors relevant to this system such as modulation of reward and intoxication.

描述(申请人提供)：疼痛是一种多方面的、复杂的疾病，影响所有人类。不幸的是，疼痛管理方面的进展收效甚微。然而，对疼痛的多个组成部分的考虑表明，以非常规部位为靶点可能会对疼痛管理领域产生强烈影响。内源性大麻素(ECB)系统是大脑和身体中的几个脂质信号系统之一。已证实该系统的组成包括两个G蛋白偶联受体，它们的信号通路，两个主要的内源性配体[花生胺(AEA)和2-花生四烯基甘油(2-AG)]，以及它们的合成和代谢途径。该系统在许多重要的中枢神经系统过程(如大脑奖赏、食欲调节、认知)中起着重要的调节作用。因此，这一系统被牵连到与这些过程相关的各种健康问题的病理生理学中也就不足为奇了，包括疼痛管理。这一应用在很大程度上是基于这样的观点，即疼痛的一个临床重要组成部分是行为抑郁(即，疼痛抑郁行为)。在人类中，这表现为缺席工作或上学，对习惯性活动缺乏兴趣，总体运动能力下降，最常与临床抑郁症有关。在动物身上，疼痛的临床表现是通过减少活动或梳理，以及对进食或社会交往的兴趣。有鉴于此，一种有前景的综合治疗疼痛的新策略是辅以关注疼痛抑郁行为和抑郁情绪。通过这一应用，我们计划使用颅内自我刺激(ICSS)和药物识别(DD)来评估ECB对小鼠疼痛抑制行为的调节。ICSS已被广泛用于研究药物对动机行为(即奖赏)和影响的调节，而DD主要用于模拟药物的主观/醉人效应。我们建议利用这些公认的可操作性程序来评估欧洲央行对疼痛诱导的行为抑郁、情感和醉酒的影响。为了补充这些行为措施，我们将通过使用成熟的神经化学分析，如质谱仪和[35S]GTPgS G蛋白结合研究，在选定的大脑区域，如伏隔核，确定情感大麻类止痛与奖励的机制特征。鉴于显然需要探索新的治疗靶点，改进现有的临床前疼痛分析，并纳入疼痛的情感成分，我们建议研究欧洲央行系统对疼痛抑郁行为的调节将满足这些需求。我们认为这些研究具有重大的公共健康影响，并在依赖于成熟的行为和神经化学措施的同时提供了很大程度的创新。总之，考虑到关于有效疼痛管理的最重要的公共卫生问题，本应用程序承诺确定欧洲央行系统是否是一种可行和有吸引力的治疗手段，以有效地减轻与疼痛管理相关的巨大社会负担。 与公共卫生相关：疼痛是一个极其重要的公共卫生问题，通常伴随着行为抑郁，导致缺勤/上学，对日常活动缺乏兴趣，总体活动减少，最常与抑郁有关。鉴于显然需要探索新的治疗靶点，改进现有的临床前疼痛检测，并纳入疼痛的情感成分，我们建议彻底评估内源性大麻素系统改善疼痛抑郁行为的能力，同时考虑与该系统相关的关键因素，如奖赏和中毒的调节。