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）：疼痛是一种影响所有人类的多方面、复杂的疾病。不幸的是，疼痛管理方面的进展取得了有限的成功。然而，考虑到疼痛的多个组成部分，表明针对非常规部位可能会强烈影响疼痛管理领域。内源性大麻素（eCB）系统是大脑和体内几种脂质信号系统之一。该系统已证实的组分包括两种g蛋白偶联受体及其信号通路，两种主要的内源性配体[anandamide （AEA）和2-花生四烯酰基甘油（2-AG）]及其合成和代谢途径。该系统在许多重要的中枢神经系统过程中起着重要的调节作用（例如，大脑奖励，食欲调节，认知）。因此，这并不奇怪，该系统已牵连到病理生理学的各种健康问题相关的这些过程，包括疼痛管理。这种应用很大程度上是基于这样一种观点，即疼痛的临床重要组成部分是行为抑郁（即疼痛抑郁行为）。在人类中，这表现为缺勤或缺学，对习惯活动缺乏兴趣，运动活动总体减少，并且通常与临床抑郁症有关。在动物中，疼痛的临床近似是通过运动或梳理的减少以及对进食或社会互动的兴趣减少来实现的。考虑到这些，一个有希望的综合治疗疼痛的新策略是对疼痛抑郁行为和抑郁情绪的辅助关注。通过这一应用，我们计划通过颅内自我刺激（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（即奖励）和影响的调节，而DD主要用于模拟药物的主观/陶醉效应。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、影响和中毒的影响。为了补充这些行为测量，我们将通过使用完善的神经化学分析，如质谱和[35S]GTPgS g蛋白结合研究，确定情感性大麻素镇痛与奖励在特定大脑区域（如与奖励和情感性疼痛有关的大脑区域伏隔核）中的机制特征。鉴于明确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要的公共卫生意义，并提供了很大程度的创新，同时依赖于完善的行为和神经化学措施。总之，考虑到有效的疼痛管理是最重要的公共卫生问题，这一应用有望确定eCB系统是否是一种可行的、有吸引力的治疗手段，以有效减少与疼痛管理相关的巨大社会负担。