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获得更安全、更有效的药物 有效的治疗方案，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一直在稳步上升，伴随着痛苦 减少和缓解焦虑是其首要适应症。此外，卡痛叶是一种含有类似咖啡的植物。 引起阿片类药物和兴奋剂作用的化合物也已广泛用于多种自我治疗 症状，包括慢性疼痛、处方阿片类药物依赖和焦虑。 用户报告说，卡痛使用的最强预测因素是大麻的使用，特别是大麻二酚（CBD）。 事实上，Kratom 和 CBD 的营销和销售并驾齐驱，以以下商店为代表： CBD Kratom© 迄今为止，还没有研究调查 Kratom 和大麻成分是否以及如何存在。 因此，了解 1) 独特且共同的药理作用至关重要。 大麻和卡痛成分，以及 2) 这些成分一起使用时是否以及如何发挥作用 沃德实验室是第一个报告非-影响的潜在功效和不良反应。 精神活性大麻成分 CBD 显着减轻化疗引起的神经性疼痛 最近，我们发现这种效应涉及与血清素 5-HT1A 受体的相互作用。 确定另一种大麻成分大麻酚（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 罗尔斯实验室于 2020 年首次报道了卡痛的生物活性生物碱帽柱木碱， 显着减少奥沙利铂引起的大鼠机械性异常性疼痛，这种效应涉及与 µ-阿片受体和肾上腺素受体因此，除了潜在的抗神经病变作用外， 这些大麻和卡痛成分也具有复杂且重叠的多药理作用。 例如，CBG 和帽柱木碱可能对 α2 肾上腺素受体具有直接拮抗作用，并且所有三种药物 化合物可能与大麻素和血清素受体相互作用，部分调节其行为效应。 对帽柱木碱和 CBG 的受体和分子靶标的了解还处于起步阶段，其程度 CBD、CBG 和帽柱木碱具有独特但重叠的作用机制仍有待研究 此外，这种独特且重叠的作用机制的可能性强烈 支持这些成分将协同作用，无论是为了增强 该 R21 申请提出了补充。 体内、离体和体外实验系统地确定受体、信号传导和基因表达 CBD、CBG 和帽柱木碱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、焦虑和体温模型。