Kratom Alkaloid Mitragynine: Therapeutic Role and Potential Utility Against Chemotherapy-Induced Peripheral Neuropathy

Abstract

Chronic neuropathic pain is a leading cause of disability worldwide and is associated with immense economic burden. Of all chronic neuropathic pain conditions, chemotherapy-induced peripheral neuropathy (CIPN) persists as a monumental public health crisis, as it is the most common comorbidity among those receiving chemotherapy for cancer treatment. CIPN is unique compared to other forms of neuropathic pain in that it is severely dose-limiting, often leading to disruption or cessation of chemotherapeutic treatment and complicating an individual’s cancer prognosis. Current pharmacological treatments for combatting CIPN are widespread yet are all accompanied with the same hindrances – they are limited in therapeutic efficacy when administered chronically and are associated with severe risk for adverse effects. Therefore, there is a clear unmet need for novel pharmacotherapies for CIPN that achieve strong therapeutic efficacy while minimizing the susceptibility to adverse events.Here, we characterize the therapeutic efficacy and pharmacological mechanisms of a novel, plant-derived alkaloid mitragynine (MG), a constituent of the kratom plant (Mitragyna speciosa) in a mouse model of CIPN. Kratom products have emerged in the US in recent years as a popular form of self-treating pain, opioid withdrawal, and symptoms of anxiety and depression, but these intended uses are largely based on anecdotal reports in humans. MG possesses a unique, mixed pharmacological profile combining opioid, adrenergic, and serotonergic properties – resembling the pharmacology of current CIPN pharmacotherapies such as antidepressants. However, the relation of these pharmacological mechanisms of MG to the context of CIPN remain under characterized. Kratom products are also commonly used in combination with cannabis products, which are also used for self-treating pain, and play a significant role in palliative care for terminal cancer patients. Yet, interactions between kratom alkaloids and cannabinoid signaling have yet to be studied in the context of CIPN. Lastly, the basis of potential utility of individual kratom constituents such as MG on anxiety- and depression-like behaviors, which are heavily comorbid in individuals with CIPN, remain understudied. The present studies were conducted to explore the role of the kratom alkaloid MG on both pain and affective behaviors associated with CIPN, at the pharmacological, cellular, and molecular level. To accomplish this, we measured 1. Contributions of opioid and adrenergic signaling mechanisms to the therapeutic efficacy of MG in a mouse model of oxaliplatin-induced mechanical hypersensitivity using pharmacological inhibition. 2. Contributions of cannabinoid signaling to the therapeutic efficacy of MG in a mouse model of oxaliplatin-induced mechanical hypersensitivity and inflammatory pain using pharmacological and genetic approaches. 3. Effects of MG on affective behaviors associated with CIPN using mouse models of the tail-suspension test, elevated zero maze, and conditioned place preference. Overall, the findings from this dissertation support the hypothesis that MG displays therapeutic efficacy against nocifensive behavior of CIPN and pain-related affective behaviors. Opioid, adrenergic, and cannabinoid mechanisms all contribute to the effect of MG on oxaliplatin-induced mechanical hypersensitivity. MG is also capable of normalizing aberrant neurotrophic factor signaling associated with CIPN. Lastly, MG produces anxiolytic effects when repeatedly administered without developing a conditioned place preference, suggesting that it achieves therapeutic efficacy in a model of CIPN without risk of adverse events.