Mitragynine Reverses Paclitaxel Chemotherapy-Induced Peripheral Neuropathy and is Mediated via Opioid Receptor Involvement

Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic side effect in patients receiving chemotherapeutic cancer treatments. Clinical use of approved analgesic drugs often does not adequately control the pathological pain arising from CIPN and does not account for potential abuse with opioid therapeutics. Mitragyna speciosa (kratom) contains the alkaloid mitragynine, which exhibits analgesic properties. However, the underlying pharmacological mechanisms that underlie these analgesic properties are complex and not completely understood. Male and female C57bl/6 mice received 8 mg/kg intraperitoneal injections of paclitaxel, a taxane class chemotherapeutic, every other day over the course of 7 days. To confirm the development of CIPN, the von Frey assay was utilized to determine the onset mechanical allodynia, which arises when a previously non-painful stimulus is perceived as painful. Intraperitoneal mitragynine and the prototypical opioid agonist morphine both dose-relatedly reversed CIPN-induced mechanical allodynia. Effective doses (ED)50 were as follows - morphine: 7.02 (6.56 - 7.51) mg/kg, mitragynine: 109.80 (104.27 - 115.62) mg/kg. Pretreatment with the opioid antagonist naltrexone 0.032 mg/kg, intraperitoneally produced a rightward shift in both morphine and mitragynine dose-response curves. Effective doses (ED)50 were as follows - naltrexone + morphine: 27.93 (24.84 - 31.40), naltrexone + mitragynine: 245.41 (211.76 - 284.39), resulting in a 3.98 and 2.24 fold shift of dose response curves, respectively. Here we show that mitragynine reverses mechanical allodynia associated with paclitaxel CIPN. We also show that opioid receptors mediate such activity, though additional data suggest a role for adrenergic and serotonin receptors as well. Mitragynine may be an effective analgesic treatment option for patients experiencing painful CIPN. © FASEB.