The Adrenergic a2 Receptor‐Mediated Discriminative‐Stimulus Effects of Mitragynine, the Primary Alkaloid in Kratom (Mitragyna Speciosa) in Rats
Authors: Reeve Morgan E. , Obeng Samuel , Oyola Francisco Leon , Behnke Mira , Restrepo Luis F. , Patel Avi , Ho Nicholas P. , Williamson Morgan R. , Gamez Jimenez Lea R. , McCurdy Christopher R. , McMahon Lance R. , Hiranita Takato 
Published: April 2020

The adrenergic α2 agonist lofexidine has been approved to treat opioid dependence while kratom has been used to mitigate opioid dependence in South Asia. The primary kratom alkaloid mitragynine has received attention due to its opioid pharmacology. However, the effects of mitragynine, including its discriminative stimulus and rate‐decreasing effects, have not been consistently blocked by the opioid antagonists naloxone and naltrexone. In contrast, the antinociceptive effects of mitragynine were blocked by the α2 antagonist idazoxan. The present study examined the opioid and α2 pharmacology of mitragynine with radioligand binding in cell membranes and drug discrimination in rats. The affinity of mitragynine at the μ‐opioid receptor (Ki=706nM) was 2‐, 10‐, 9‐ and 5‐fold higher than its affinity at the k‐ and d‐opioid, and a2A and a2C receptors, respectively, labelled with [3H]DAMGO, [3H]U69593, [3H]DADLE, [3H]RX821002 and [3H]RX821002. In rats discriminating mitragynine (32mg/kg, i.p.), its ED50 value to produce mitragynine‐lever responding was 16mg/kg. The d‐, k‐, and μ‐opioid receptor agonists SNC80, U69593, and morphine, respectively, produced no greater than 60% mitragynine‐lever responding. The a2 agonists lofexidine and clonidine produced 74% and 45% mitragynine‐lever responding, respectively; the a2 antagonists yohimbine and atipamezole produced 40% and 46% mitragynine‐lever responding, respectively. Yohimbine (3.2mg/kg) and naltrexone (0.032mg/kg) antagonized the mitragynine discriminative stimulus, i.e., increased its ED50 by 2‐ and 5‐fold, respectively. Lofexidine (0.1mg/kg) and clonidine (0.32mg/kg) reduced the ED50 of the mitragynine discriminative stimulus by 9‐ and 5‐fold, respectively. In separate groups of rats discriminating either morphine (3.2mg/kg) or lofexidine (0.032mg/kg), mitragynine produced 72% morphine‐ and 100% lofexidine‐lever responding (ED50s=11 and 15mg/kg). In the morphine‐trained rats, 0.032mg/kg naltrexone produced an 8‐fold rightward shift in the morphine discrimination dose‐effect function. In contrast, yohimbine, lofexidine and clonidine produced no more than a 2‐fold change in the morphine discrimination ED50. The pharmacological selectivity of the effects of mitragynine as a test drug was further assessed using separate groups of rats discriminating either the adrenergic a1 agonist phenylephrine (3.2mg/kg) or the cannabinoid agonist THC (3.2mg/kg). Mitragynine produced 100% phenylephrine‐lever responding (ED50=19mg/kg), but only 36% THC‐lever responding. Mitragynine had comparable binding affinity at opioid and a2 receptors in the micromolar range in vitro, and appeared to exhibit comparable μ‐opioid and a2 receptor agonist activity in vivo. By combining two separate pharmacologies in a single drug entity which otherwise requires treatment with two or more FDA approved drugs (e.g., methadone and lofexidine), mitragynine and its analogs may represent a useful approach for treating opioid use disorders.Support or Funding InformationNIDA grants DA23205 and DA48353.