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.

严重疼痛的治疗是一个重大的临床挑战，使用传统的 止痛药的副作用有限。一种替代策略针对大麻素 通过抑制单酰基甘油脂肪酶（MAGL）间接抑制CBRs， 其降解内源性大麻素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的优点， 靶向神经元的2-AG释放和CBR激活在时间上精确增加 由疼痛激活的神经回路更具体地说，这一更新申请建议 研究急性和慢性疼痛产生的镇痛作用的表达和机制， 在开发的新型临床前程序中长期递送MAGL抑制剂， 在最初的资助期间验证，以评估疼痛抑郁行为， 疼痛的临床相关表现。最重要的假设是， 抑制将安全有效地缓解疼痛相关的临床相关体征， 通过2-AG介导的缓冲CNS活性的CB 1 R活化的行为抑制 疼痛回路目的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， 和痛苦压抑的行为我们假设MAGL抑制剂会产生 所有试验中的镇痛作用最小，初步数据支持这一点 假说.目标2将检验MAGL抑制剂缓解疼痛相关的假设 通过CBR介导的缓解疼痛相关抑郁的行为抑郁 中脑边缘多巴胺回路我们建议定位神经元活动的标记， 测量候选区域中的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的中脑边缘多巴胺释放的相关抑制， 以及脑定位MAGL抑制剂注射来缓解疼痛抑郁行为。 目的3将评估重复给予MAGL抑制剂对两种疾病的影响。 行为和CB 1 R调节在一个新的模型慢性发作性疼痛。我们假设 MAGL抑制将产生持续缓解疼痛抑郁行为， 介导缓解的脑区域中的显著CB 1 R脱敏和/或下调 痛苦压抑的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。