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: 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
• 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' 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

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.

治疗剧烈疼痛是一个重大的临床挑战，使用传统的 止痛药受到副作用的限制。一种针对大麻素的替代策略 受体(CBRs)通过抑制单酰基甘油脂肪酶(MAGL)间接作用， 它降解内源性大麻素2-花生四烯酸甘油(2-AG)。我们 提出MAGL抑制剂在解剖学上具有产生和 针对神经细胞的2-AG释放和CBR激活在时间上的精确增加 由疼痛激活的回路。更具体地说，这份续签申请提议 急性和慢性疼痛的表达及机制研究 MAGL抑制剂在新的临床前程序中的慢性给药 在最初的资助期内进行验证，以评估建模的疼痛抑郁行为 疼痛的临床相关表现。最重要的假设是MAGL 抑制将安全有效地缓解疼痛相关的临床相关体征 2-AG介导的中枢神经系统缓冲活性CB1Rs的激活引起的行为抑制 痛觉回路。目标1将比较MAGL抑制剂、直接CBR激动剂、 以及一系列系统的对照药物在疼痛刺激的补充分析中 以及痛苦抑郁的行为。我们假设MAGL抑制剂会产生 所有试验中的止痛副作用都很小，初步数据支持这一点 假设。Aim 2将验证MAGL抑制剂缓解疼痛相关的假设 CBR介导的行为抑郁缓解疼痛相关性抑郁 中脑边缘多巴胺环路。我们建议将神经元活动的标志物本地化并 测量用于调节疼痛抑郁行为的候选区域的ECB水平。 此外，我们建议检查MAGL抑制剂缓解疼痛的有效性- 体内微透析法评估中脑边缘多巴胺释放的相关抑制， 以及脑部靶点注射MAGL抑制剂以缓解疼痛抑郁行为。 AIM 3将评估重复使用MAGL抑制剂对这两种药物的影响 慢性阵发性疼痛新模型的行为和CB1R调节。我们假设 MAGL抑制将产生疼痛抑郁行为的持续缓解，而不是 介导缓解的脑区CB1R显著脱敏和/或下调 痛苦抑郁的行为。成功完成拟议的研究将使 进一步考虑将MAGL抑制剂作为治疗疼痛的可行选择。