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：
9403737
负责人：
Sidney S Negus
金额：
$ 53.41万
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：
2011-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403737
关键词：
2-arachidonylglycerol Absence of pain sensation Acids Acute Acute Pain Adverse effects Agonist Analgesics Anatomy Area Behavior Behavioral Behavioral Assay Biological Assay Brain Brain Stem Buffers CNR1 gene CNR2 gene Cannabinoids Chronic Clinical Clinical Treatment Clinical Trials Data Depressed mood Diagnosis Dopamine Down-Regulation Drug Controls Effectiveness Endocannabinoids Enzyme Inhibitor Drugs Enzymes Exhibits FAAH inhibitor Frequencies Freund&apos s Adjuvant Funding Human Injection of therapeutic agent Intraperitoneal Injections Locomotion MAGL inhibitor Marijuana Measures Mediating Mental Depression Microdialysis Modeling Monoacylglycerol Lipases Moods Mus Neurons Nociception Nucleus Accumbens Opioid Pain Pain management Pathway interactions Pharmaceutical Preparations Pharmacology Procedures Receptor Activation Regulation Resistance Series Signal Transduction Site Specificity Stimulus Stretching Tegmentum Mesencephali Testing Tetrahydrocannabinol Time Translations Ventral Tegmental Area Veterinary Medicine Withdrawal anandamide cannabinoid drug cannabinoid receptor clinical efficacy clinically relevant desensitization dopaminergic neuron drug development fatty acid amide hydrolase feeding functional disability gamma-Aminobutyric Acid improved in vivo intraperitoneal mu opioid receptors neural circuit neurochemistry neuromechanism neurotransmission novel pain behavior parabrachial nucleus pre-clinical pre-clinical research receptor response

项目摘要

Treatment of severe pain is a significant clinical challenge, and use of traditional analgesics is limited by side effects. One alternative strategy targets cannabinoid receptors (CBRs) indirectly by inhibiting the enzyme monoacylglycerol lipase (MAGL), which degrades the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG). We propose that MAGL inhibitors have the advantage of producing anatomically and temporally precise increases in 2-AG release and CBR activation targeted to neural circuits activated by pain. More specifically, this renewal application proposes to investigate expression and mechanisms of analgesic effects produced by acute and chronic delivery of MAGL inhibitors in novel preclinical procedures developed and validated during the initial funding period to assess pain-depressed behaviors that model clinically relevant manifestations of pain. The overarching hypothesis is that MAGL inhibition will safely and effectively ease clinically relevant signs of pain-related behavioral depression via 2-AG-mediated activation of CB1Rs that buffer activity in CNS pain circuits. Aim 1 will compare the effects of MAGL inhibitors, direct CBR agonists, and a systematic series of control drugs in complementary assays of pain-stimulated and pain-depressed behavior. We hypothesize that MAGL inhibitors will produce analgesia in all assays with minimal side effects, and preliminary data support this hypothesis. Aim 2 will test the hypothesis that MAGL inhibitors alleviate pain-related depression of behavior by CBR-mediated alleviation of pain-related depression of mesolimbic dopamine circuits. We propose to localize markers of neuronal activity and measure eCB levels in candidate regions for modulating pain-depressed behavior. Additionally, we propose to examine effectiveness of MAGL inhibitors to relieve pain- related depression of mesolimbic dopamine release assessed by in vivo microdialysis, and of brain site-targeted MAGL inhibitor injections to alleviate pain-depressed behavior. Aim 3 will assess the effects of repeatedly administered MAGL inhibitors on both behavior and CB1R regulation in a novel model of chronic episodic pain. We hypothesize that MAGL inhibition will produce sustained relief of pain-depressed behavior without significant CB1R desensitization and/or downregulation in brain areas that mediate relief of pain-depressed behavior. Successful completion of the proposed studies will inform further consideration of MAGL inhibitors as viable options for pain treatment.

严重疼痛的治疗是一项重大的临床挑战，使用传统的方法镇痛药受到副作用的限制。一种针对大麻素的替代策略通过抑制单酰基甘油脂肪酶（MAGL）间接作用于受体（CBR），它降解内源性大麻素 2-花生四烯酰甘油 (2-AG)。我们提出 MAGL 抑制剂具有在解剖学上产生和 2-AG 释放和针对神经的 CBR 激活在时间上精确增加疼痛激活的回路。更具体地说，该续展申请建议研究急性和镇痛产生的镇痛作用的表达和机制在开发和开发的新型临床前程序中长期递送 MAGL 抑制剂在初始资助期间进行验证，以评估模拟的疼痛抑郁行为疼痛的临床相关表现。总体假设是 MAGL 抑制将安全有效地缓解与疼痛相关的临床相关症状通过 2-AG 介导的 CB1R 激活（缓冲 CNS 活动）导致行为抑郁疼痛回路。目标 1 将比较 MAGL 抑制剂、直接 CBR 激动剂、以及一系列系统性对照药物，用于疼痛刺激的补充分析和疼痛抑郁行为。我们假设 MAGL 抑制剂会产生所有检测中的镇痛作用最小，副作用最小，初步数据支持这一点假设。目标 2 将检验 MAGL 抑制剂减轻疼痛相关的假设通过 CBR 介导缓解疼痛相关抑郁症来抑制行为中脑边缘多巴胺回路。我们建议定位神经元活动的标记并测量候选区域的 eCB 水平以调节疼痛抑制行为。此外，我们建议检查 MAGL 抑制剂缓解疼痛的有效性通过体内微透析评估中脑边缘多巴胺释放的相关抑制，以及针对大脑部位的 MAGL 抑制剂注射以减轻疼痛抑制行为。目标 3 将评估重复施用 MAGL 抑制剂对两者的影响慢性阵发性疼痛新型模型中的行为和 CB1R 调节。我们假设 MAGL 抑制将持续缓解疼痛抑制行为，而无需 CB1R 显着脱敏和/或下调可介导缓解的大脑区域疼痛抑郁行为。成功完成拟议的研究将告知进一步考虑 MAGL 抑制剂作为疼痛治疗的可行选择。