Neurotrophic and Adrenergic Mechanisms Contribute to the Anti‐Allodynic Efficacy of the Kratom Alkaloid Mitragynine Against Chemotherapy‐Induced Peripheral Neuropathy

Abstract

Mitragyna speciosa (kratom) is a coffee‐like plant containing several biologically active alkaloids, with mitragynine (MG) being the most prevalent. MG has a mixed pharmacological profile, containing both opioid and stimulant‐like effects. Chemotherapy‐induced peripheral neuropathy (CIPN) is a progressive and dose‐limiting chronic pain condition characterized by sensory disturbances such as spontaneous pain, hyperalgesia, and allodynia. Mechanistically, brain‐derived neurotrophic factor (BDNF) plays a critical role in CIPN pathophysiology, as its expression contributes to dorsal horn hyperexcitability. Currently, antidepressants (TCA’s, SNRI’s) are first‐line neuropathic pain medications, achieving their therapeutic effect through enhanced adrenergic neurotransmission. Yet, clinical outcomes of CIPN remain poor, proving an unmet need for better pharmacological interventions. Therefore, we wished to test the therapeutic efficacy of MG in a rodent model of CIPN, and to investigate the involvement of adrenergic and BDNF signaling. Given the role of antidepressants in treating CIPN, we also wished to explore antidepressant properties of MG in response to oxaliplatin exposure. Overall, it was hypothesized that MG would reduce oxaliplatin‐induced mechanical sensitivity through a mechanism involving α‐adrenoceptor activation and BDNF signaling and would produce antidepressant‐like effects in mice with CIPN.Baseline mechanical sensitivity was assayed in male adult C57/BL6 mice with von Frey monofilaments, followed by a single injection of the chemotherapeutic oxaliplatin (6 mg/kg, IP). Mice then received MG (1‐20 mg/kg, IP) alone or in combination with the α2‐adrenoceptor antagonist yohimbine (5 mg/kg, IP), or vehicle for 6 days. Mechanical sensitivity was again measured on day 7 post‐oxaliplatin treatment. Brains and lumbar dorsal spinal cord were collected immediately following day 7 behavioral assessment and mRNA expression of BDNF, ADRA2A, and ADRA2C was quantified by RT‐qPCR. In a separate cohort, mice which received oxaliplatin or MG alone or in combination were subjected to the tail suspension test (TST) to characterize the potential effects of oxaliplatin and MG on depressive‐like behaviors. Results indicated that repeated MG exposure produced a significant anti‐allodynic effect at doses of 5 and 10 mg/kg compared to controls. Additionally, yohimbine pretreatment completely blocked the anti‐allodynic effect produced by MG. Oxaliplatin alone significantly increased mRNA expression of BDNF in the periaqueductal gray (PAG), which was normalized by MG. In the TST, oxaliplatin alone did not affect immobility, nor did MG alone or in combination with oxaliplatin have any effect on immobility times. Overall, these findings suggest oxaliplatin produces neuropathic pain without developing depression‐like behaviors. Furthermore, MG achieves its therapeutic efficacy through α2‐adrenoceptor activation, as well as regulation of supraspinal BDNF expression, without producing any antidepressant‐like effects.