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

随着阿片类药物危机在美国的持续，那些遭受慢性疼痛的人看起来更安全、更 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一直在稳步上升，伴随着疼痛 减少和缓解焦虑是其首要适应症。此外，Kratom是一种类似咖啡的植物，含有 导致阿片类药物和兴奋剂作用的化合物也因几种自我治疗而广受欢迎 症状，包括慢性疼痛、处方阿片依赖和焦虑。最近对Kratom的一项调查 用户报告说，Krtom使用的最强预测因素是大麻使用，特别是大麻二醇(CBD)。 的确，Krtom和CBD的营销和销售并驾齐驱，以以下商店为代表 CBD Kratom©.到目前为止，还没有研究调查Krtom和Cannabis的成分是否以及如何 可能会相互作用。因此，重要的是要了解1)独特的和共同的药理作用 大麻和Krtom成分，以及2)这些成分一起使用时是否以及如何发挥作用 影响潜在疗效和不良反应。沃德实验室是第一个报告非 精神活性大麻成分CBD显著减轻化疗所致的神经病理性疼痛 这种作用涉及到与5-羟色胺5-HT1A受体的相互作用。最近，我们有 另一种大麻成分大麻酚(CBG)也能降低机械敏感性。 奥沙利铂相关神经病理性疼痛的小鼠模型，这次是通过大麻素和肾上腺素能 机械装置。罗尔斯实验室在2020年首次报道了Kratom的生物活性生物碱，三叶草碱， 显著降低奥沙利铂诱导的大鼠机械性痛觉异常，这一效应涉及与 微阿片受体和肾上腺素能受体。因此，除了它们潜在的抗神经病作用外， 这些大麻和Krtom成分也有复杂和重叠的多药理作用。为 例如，CBG和米托吗宁可能对α-2肾上腺素受体有直接拮抗作用，而且这三种受体都有 化合物可能与大麻素和5-羟色胺受体相互作用，部分地调节它们的行为效应。 对米曲林和CBG的受体和分子靶点的了解还处于初级阶段，以及 CBD、CBG和MITRAGINE具有独特的作用机制，但相互重叠的作用机制仍有待研究 对其进行了系统研究。此外，这种独特和重叠的行动机制的可能性很大 支持这些组成部分将协同工作，无论是为了加强 推定的治疗效果或加重不良反应。此R21应用程序在以下方面提供了补充 系统地确定受体、信号和基因表达的体内、体外和体外实验 CBD、CBG和三尖杉酯碱在小鼠体内的相互作用及其相互作用 神经性疼痛、炎症性疼痛、焦虑和体温的模型。

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.