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（由申请人提供）：疼痛是一种影响全人类的多方面、复杂的疾病。不幸的是，疼痛管理方面的进展却取得了有限的成功。然而，对疼痛多种成分的考虑表明，针对非常规部位可能会对疼痛管理领域产生强烈影响。内源性大麻素 (eCB) 系统是大脑和体内的几种脂质信号系统之一。该系统经过验证的组件包括两个 G 蛋白偶联受体、它们的信号传导途径、两个主要内源性配体 [anandamide (AEA) 和 2-花生四烯酸甘油 (2-AG)] 及其合成和代谢途径。该系统在许多关键的中枢神经系统过程（例如大脑奖赏、食欲调节、认知）中发挥着重要的调节作用。因此，该系统涉及与这些过程相关的各种健康问题的病理生理学，包括疼痛管理，也就不足为奇了。该应用主要基于以下观点：疼痛的临床重要组成部分是行为抑郁（即疼痛抑制行为）。对于人类来说，这表现为缺勤或缺课、对日常活动缺乏兴趣、运动活动总体下降，并且最常与临床抑郁症相关。在动物中，疼痛的临床近似表现是运动或梳理毛发的减少以及对进食或社交互动的兴趣的减少。鉴于这些，综合治疗疼痛的一个有前途的新策略是辅助关注疼痛抑郁行为和抑郁情绪。通过此应用，我们计划使用小鼠颅内自我刺激 (ICSS) 和药物辨别 (DD) 来评估 eCB 对疼痛抑制行为的调节。 ICSS 已广泛用于研究药物对动机行为（即奖励）和影响的调节，而 DD 主要用于模拟药物的主观/中毒效应。我们建议利用这些完善的操作程序来评估 eCB 对疼痛引起的行为抑郁、情感和中毒的影响。为了补充这些行为测量，我们将通过使用成熟的神经化学分析（例如质谱法）来确定选定大脑区域（例如伏隔核，与奖励和情感疼痛有关的大脑区域）中情感大麻素镇痛与奖励的机制特征和[35S]GTPgS G 蛋白结合研究。鉴于明确需要探索新的治疗靶点，改进现有的临床前疼痛测定，并纳入疼痛的情感成分，我们建议研究 eCB 系统对疼痛抑制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卫生影响，并在依赖于完善的行为和神经化学测量的同时提供了很大程度的创新。总之，考虑到有效疼痛管理的首要公共卫生问题，该应用有望确定 eCB 系统是否是一种可行且有吸引力的治疗手段，可以有效减轻与疼痛管理相关的巨大社会负担。 公共卫生相关性：疼痛是最重要的公共卫生问题，通常伴有行为抑郁，导致缺勤/上学、对日常活动缺乏兴趣、活动总体减少，并且通常与抑郁有关。鉴于明确需要探索新的治疗靶点，改进现有的临床前疼痛测定，并纳入疼痛的情感成分，我们建议对内源性大麻素系统改善疼痛抑制行为的能力进行全面评估，同时考虑相关的关键因素对该系统的影响，例如奖赏和中毒的调节。