Kratom and Cannabinoid Constituents: Mechanisms and Interactive Effects in Neuropathic Pain

卡痛和大麻素成分：神经性疼痛的机制和相互作用

• 批准号: 10745835
• 负责人: SCOTT M. RAWLS
• 金额: $ 43.37万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745835
• 关键词: Adrenergic Agents; Adrenergic Receptor; Adverse effects; Affinity; Alkaloids; Anxiety; Arrestins; Attenuated; Behavior; Behavioral; Binding; Biological Assay; Black race; Body Temperature; C57BL/6 Mouse; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cells; Coffee; Complex; Coupled; Data; Dependence; Development; Dorsal; Dose; Exploratory/Developmental Grant; Face; Female; Formalin; GTP-Binding Proteins; Gene Expression; Gene Expression Profiling; Genes; Harvest; In Vitro; Laboratories; Ligands; Marketing; Mechanics; Mediating; Medical; Mitragyna; Molecular Target; Motivation; Mus; Names; Natural Products; Natural Remedy; Neuropathy; Opioid; Opioid Receptor; Pain; Pain Measurement; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Plants; Prevalence; Rattus; Receptor Signaling; Regimen; Reporting; Rodent; Rodent Model; Safety; Sales; Series; Serotonin; Serotonin Receptor 5-HT1A; Side; Signal Transduction; Specificity; Spinal Cord; Spinal Ganglia; Statutes and Laws; Stimulant; Surveys; Symptoms; Therapeutic Effect; Time; Tissue Harvesting; Transfection; Work; antagonist; anxiety reduction; anxiety-like behavior; attenuation; cannabigerol; cannabinoid receptor; chemotherapy; chronic pain; differential expression; effective therapy; experimental study; in vivo; infancy; inflammatory pain; insight; male; marijuana use; marijuana use disorder; mechanical allodynia; midbrain central gray substance; mouse model; opioid epidemic; opioid use; oxaliplatin; pain model; pain reduction; painful neuropathy; pharmacologic; prescription opioid addiction; prevent; receptor; recruit; serotonin receptor; ward

As the opioid crisis continues in the US, those suffering from chronic pain look to perceived safer and more effective treatment options, including natural remedies. The scientific evidence, practice, and legislation surrounding the medical use of Cannabis has been steadily on the rise over the last several decades, with pain reduction and alleviation of anxiety as its top indications. In addition, Kratom, a coffee-like plant containing compounds that cause opioid and stimulant effects, has also gained popularity for self-treatment of several symptoms, including chronic pain, prescription opioid dependence, and anxiety. A recent survey of Kratom users reported that the strongest predictor of Kratom use was Cannabis use, specifically cannabidiol (CBD). Indeed, the marketing and sale of Kratom and CBD side by side is on the rise, represented by shops such as CBD Kratom©. To date there are no studies to investigate whether and how Kratom and Cannabis constituents may interact. Therefore, it is critical to understand 1) the unique and shared pharmacological actions of Cannabis and Kratom constituents, and 2) whether and how these constituents may act when used together to impact potential efficacy and adverse effects. The Ward laboratory was the first to report that the non- psychoactive cannabis constituent CBD significantly attenuated chemotherapy-induced neuropathic pain in mice, and this effect involved interactions with the serotonin 5-HT1A receptor. Most recently, we have determined that another Cannabis constituent cannabigerol (CBG) also attenuates mechanical sensitivity in a mouse model of oxaliplatin associated neuropathic pain, this time through cannabinoid and adrenergic mechanisms. The Rawls laboratory first reported in 2020 that the bioactive alkaloid of Kratom, mitragynine, significantly reduced oxaliplatin-induced mechanical allodynia in rats, and this effect involved interactions with µ-opioid receptors and adrenergic receptors. Therefore, in addition to their potential anti-neuropathic effects, these Cannabis and Kratom constituents also share a complex and overlapping polypharmacology. For example, CBG and mitragynine may share direct antagonistic effects on α2 adrenoreceptors, and all three compounds may interact with cannabinoid and serotonin receptors to in part mediate their behavioral effects. Understanding of the receptor and molecular targets for mitragynine and CBG is at its infancy, and the extent to which CBD, CBG, and mitragynine possess unique but overlapping mechanisms of action remains to be systematically studied. Furthermore, this likelihood of unique and overlapping mechanisms of action strongly supports that these constituents will work synergistically in combination, whether it be toward potentiating putative therapeutic effects or exacerbating adverse effects. This R21 application proposes complementary in vivo, ex vivo, and in vitro experiments to systematically determine receptor, signaling, and gene expression interactions underlying the effects of CBD, CBG, and mitragynine, and their interactive effects in mouse models of neuropathic pain, inflammatory pain, anxiety, and body temperature.

随着美国阿片类药物危机的持续，那些患有慢性疼痛的人希望被认为更安全、更安全 有效的治疗选择，包括自然疗法。科学证据、实践和立法 在过去的几十年里，围绕大麻的医疗用途的争论一直在稳步上升， 减少和缓解焦虑作为其首要指标。此外，Kratom，一种类似咖啡的植物，含有 引起阿片样物质和兴奋剂作用的化合物，也已经流行于几种 症状，包括慢性疼痛，处方阿片类药物依赖和焦虑。Kratom最近的调查 用户报告说，Kratom使用的最强预测是大麻的使用，特别是大麻二酚（CBD）. 事实上，Kratom和CBD并排的营销和销售正在上升，由商店，如 CBD Kratom©.到目前为止，没有研究调查是否以及如何Kratom和大麻成分 可以互动。因此，了解1）独特和共享的药理作用是至关重要的 大麻和Kratom成分，和2）是否以及如何这些成分可能会起作用时，一起使用， 影响潜在功效和副作用。沃德实验室是第一个报告说，非 精神活性大麻成分CBD显着减弱化疗诱导的神经性疼痛， 这种效应涉及与5-羟色胺5-HT 1A受体的相互作用。最近，我们 确定另一种大麻成分大麻萜酚（CBG）也会减弱机械敏感性， 奥沙利铂相关神经性疼痛的小鼠模型，这次是通过大麻素和肾上腺素能 机制等罗尔斯实验室于2020年首次报道，Kratom的生物活性生物碱，mitragynine， 显著降低大鼠中奥沙利铂诱导的机械性异常性疼痛，该效应涉及与 μ-阿片受体和肾上腺素能受体。因此，除了其潜在的抗神经病作用外， 这些大麻和Kratom成分也共享一个复杂的和重叠的多药理学.为 例如，CBG和mitragynine可能对α2肾上腺素受体具有直接拮抗作用， 化合物可与大麻素和5-羟色胺受体相互作用，以部分介导它们的行为效应。 对mitragynine和CBG的受体和分子靶点的理解还处于起步阶段， CBD，CBG和mitragynine具有独特的但重叠的作用机制， 系统地研究。此外，这种独特和重叠的作用机制的可能性强烈 支持这些成分将协同工作的组合，无论是对增强 推定的治疗效果或恶化的副作用。该R21应用程序建议在以下方面进行补充： 系统测定受体、信号传导和基因表达的体内、离体和体外实验 CBD，CBG和mitragynine作用的相互作用及其在小鼠中的相互作用 神经性疼痛、炎性疼痛、焦虑和体温的模型。