Endocannabinoid modulation of pain-depressed behavior

内源性大麻素对疼痛抑制行为的调节

基本信息

批准号：
8287528
负责人：
Sidney S Negus
金额：
$ 33.64万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
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/8287528
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

项目摘要

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，疼痛管理方面的进展取得了有限的成功。但是，对多种疼痛组成部分的考虑表明，针对非规定部位可能会强烈影响疼痛管理领域。内源性大麻素（ECB）系统是大脑和体内的几个脂质信号系统之一。该系统的经过验证的组件包括两个G蛋白偶联受体，其信号通路，两个主要的内源配体[Anandamide（AEA）和2-芳基多酰基甘油（2-AG）]以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中起重要的调节作用（例如，大脑奖励，食欲调节，认知）。因此，毫不奇怪，该系统已与与这些过程有关的各种健康问题（包括疼痛管理）的病理生理牵涉。该应用在很大程度上基于这样的想法：疼痛的临床意义成分是行为抑郁症（即疼痛抑郁的行为）。在人类中，这表明这表明了工作或学校缺席，对习惯活动缺乏兴趣，运动活动的总体下降，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修饰以及对喂养或社交相互作用的兴趣。鉴于这些，全面治疗疼痛的新策略是对痛苦抑郁的行为和情绪低落的辅助。通过此应用，我们计划使用小鼠中颅内自我刺激（ICS）和药物歧视（DD）评估欧洲央行对疼痛抑郁的行为的调节。 ICS已被广泛用于研究动机行为的调节（即奖励），并受到药物的影响，而DD主要用于对药物的主观/陶醉作用进行建模。我们建议利用这些良好的操作程序来评估欧洲央行对疼痛引起的行为抑郁，情感和中毒的影响。为了补充这些行为措施，我们将通过使用良好的神经化学分析（如质谱法和质谱法和gtpgs gtpgs gtpgs gtpgs gtpgs gtpote gotote contucting contign conseption措施，例如伏伏核核者（伏伏核）的精选大脑区域的机理特征与奖励的机理特征。鉴于明确需要探索新颖的治疗靶标，改善现有的临床前疼痛测定并纳入疼痛的情感成分，我们建议研究欧洲央行系统对疼痛抑郁的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，并在依靠良好的行为和神经化学措施的同时提供了大量的创新。总而言之，考虑到有关有效疼痛管理的最高公共卫生问题，该应用程序有望确定欧洲央行系统是否是可行且有吸引力的治疗方法，可以有效减轻与疼痛管理相关的巨大社会负担。