Pharmacological Characterization of Mitragynine, the Primary Constituent in Kratom (Mitragyna Speciosa)

Abstract

Kratom (Mitragyna Speciosa) and associated commercial products are to self‐treat pain and opioid dependence. The Drug Enforcement Agency and Food and Drug Administration continue to monitor this unregulated product. Mitragynine is the primary alkaloid constituent of kratom. In vitro radioligand binding assays demonstrate that mitragynine has affinity for mu‐opioid receptors (MORs), and lesser affinity for alpha2‐adrenergic receptors. The present study characterized the pharmacological effects of mitragynine using various behavioral and physiological measurements in rats. In rats trained to discriminate morphine (3.2 mg/kg, i.p.) from vehicle (20% Tween 80 in saline) under a standard two‐lever operant conditioning procedure using a food reinforcer, morphine (0.32–3.2 mg/kg) and the MOR agonist fentanyl (0.0032–0.178 mg/kg) produced dose‐dependent increases in morphine‐lever responding. Mitragynine produced a maximum of 70% morphine‐lever responding up to a dose (56 mg/kg) that markedly decreased response rate. In rats trained to discriminate mitragynine (32 mg/kg, i.p.) from vehicle (20% Tween 80 in saline), mitragynine (5.6–56 mg/kg) dose‐dependently increased mitragynine‐lever responding. Morphine (up to 32 mg/kg) and fentanyl (up to 0.178 mg/kg) produced a maximum of 75% mitragynine‐lever responding. The opioid antagonist naltrexone (0.032 mg/kg) significantly antagonized both training drugs. The alpha2‐adrenergic receptor agonist clonidine (0.0178–0.178 mg/kg) produced a maximum of 38% and 58% druglever responding in morphine‐ and mitragynine‐trained rats, respectively. The alpha2‐adrenergic receptor antagonist yohimbine (1–10 mg/kg, i.p.) produced a maximum of 21% and 48% druglever responding in the respective discriminations. Yohimbine (3.2 mg/kg) significantly antagonized the discriminative stimulus effects of the training doses of morphine and mitragynine. In a warm water (50°C) tail‐withdrawal procedure, morphine (10–56 mg/kg) dosedependently decreased tail‐withdrawal latency up to 100% maximal possible effect. The maximum possible effect of mitragynine (17.8–56 mg/kg) was 40% up to the largest dose that could be safely studied. When measuring rectal temperature, clonidine (0.01–0.1 mg/kg) and the alpha2‐adrenergic receptor agonist lofexidine (0.056–0.56 mg/kg) produced dose‐dependent hypothermia; the hypothermic effects of both clonidine and lofexidine were antagonized by yohimbine (1 mg/kg). Mitragynine did not significantly alter rectal temperature up to a dose of 56 mg/kg. Consistent with in vitro and ex vivo assays, the current results suggests that mitragynine functions as a low efficacy MOR agonist with discriminative stimulus effects that are overlapping yet distinct from those of morphine. These data suggest that alpha2‐adrenergic receptors represent a component of mitragynine's pharmacological mechanism of action in vivo.Support or Funding InformationSupported by NIDA DA25267 and DA48353.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.