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: 8851547
• 负责人: Sidney S Negus
• 金额: $ 33.13万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851547
• 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; Evaluation; Exhibits; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Grooming; Guanosine Triphosphate; Health; Human; Injection of therapeutic agent; Intoxication; Lactic acid; Ligands; Lipids; Locomotion; Major Depressive Disorder; Marijuana; 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; marijuana use; 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.

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疾病。不幸的是，疼痛管理的进展取得了有限的成功。然而，对疼痛的多个组成部分的考虑表明，靶向非传统部位可能会强烈影响疼痛管理领域。内源性大麻素（eCB）系统是大脑和身体中的几种脂质信号传导系统之一。该系统的验证组件包括两个G蛋白偶联受体，其信号传导途径，两个主要的内源性配体[花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）]，以及它们的合成和代谢途径。该系统在许多关键的CNS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，该系统已牵连在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。该应用主要基于疼痛的临床显著成分是行为抑郁（即，疼痛抑郁行为）。在人类中，这表现为缺席工作或学校，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减少运动或梳理以及对进食或社会互动的兴趣。鉴于这些，一个有前途的新战略，综合治疗疼痛是一个辅助重点疼痛抑郁行为和抑郁情绪。通过该应用，我们计划在小鼠中使用颅内自我刺激（ICSS）和药物辨别（DD）评估eCB对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/中毒效应。我们建议利用这些成熟的操作程序来评估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[35 S]GTPgS G-蛋白结合研究，确定在选定的脑区，如丘脑核，涉及奖励和情感疼痛的脑区中情感大麻素镇痛与奖励的机制特征。鉴于明确需要探索新的治疗靶点，改善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系统的疼痛抑制行为的调制将满足这些需求。我们认为这些研究具有重大的公共卫生意义，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，考虑到关于有效疼痛管理的最重要的公共卫生问题，本申请有望确定eCB系统是否是一种可行且有吸引力的治疗方法，以有效减少与疼痛管理相关的巨大社会负担。