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

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更安全，更安全

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.