The Lofexidine‐Like Discriminative Effects of the Primary Kratom Alkaloid Mitragynine in Rats

Abstract

The primary kratom alkaloid mitragynine has received attention due to its µ-opioid receptor (MOR) activity; however, the antinociceptive effects of mitragynine in mice were blocked by the adrenergic-α2 receptor (Aα2R) antagonist idazoxan. Here we examined the Aα2R pharmacology of mitragynine with radioligand receptor binding in human cell membranes and drug discrimination, the hot plate test (antinociception), and measurement of rectal temperature (hypothermia) in rats. The affinity of mitragynine at human MOR (Ki=706 nM) was 2- to 10-fold higher than its affinity at other opioid (k and d) and adrenergic (a2A and a2C) receptors. In rats discriminating mitragynine (32mg/kg, i.p.) from vehicle, MOR agonists (morphine, fentanyl, and methadone), Aα2R agonists (lofexidine and clonidine), and Aα2R antagonists (yohimbine and atipamezole) produced up to 84%, 74%, and 40% drug-lever responding, respectively. In rats discriminating lofexidine (0.032 mg/kg, i.p.) from vehicle, the Aα2R agonists (lofexidine and clonidine), mitragynine, Aα2R antagonists (yohimbine and atipamezole), and morphine produced up to 97%, 95%, 7.1%, and 7.3% drug-lever responding, respectively. In rats discriminating morphine (3.2mg/kg, i.p.) from vehicle, MOR agonists (morphine, fentanyl, and methadone) produced at least 98% drug-lever responding, and mitragynine produced up to 72% drug-lever responding. The Aα2R agonists (lofexidine and clonidine) and antagonists (yohimbine and atipamezole) produced a maximum of 30% drug-lever responding. The full substitution of mitragynine for lofexidine was pharmacologically specific. In rats discriminating the cannabinoid receptor agonist D9-THC (3.2mg/kg, i.p.) from vehicle, another cannabinoid receptor agonist CP55,940, mitragynine, and morphine produced up to 99%, 23%, and 18.4% drug-lever responding, respectively. In the hotplate (52°C) test, the MOR agonists (morphine, fentanyl, and methadone) produced at least 90 % maximum possible effects, whereas MG was ineffective. Aα2R agonists (lofexidine and clonidine) produced up to 63% maximum possible effects, and the Aα2R antagonists (yohimbine and atipamezole) produced up to 85% maximum possible effects. The cannabinoid receptor agonists (D9-THC and CP55,940) produced up to 67% maximum possible effects. Rectal temperature was decreased by 0.3°C for the MOR agonists, 1.0°C for Mitragynine, up to 4.8°C for the Aα2R agonists, up to 3.4°C for the Aα2R antagonists, and up to 3.8°C for the cannabinoid receptor agonists. Atipamezole antagonized the discriminative stimulus effects of mitragynine as well as lofexidine but not the discriminative or antinociceptive effects of morphine. Both lofexidine and clonidine potentiated mitragynine discrimination but not the discriminative or antinociceptive effects of morphine. These results suggest that mitragynine exerts its in vivo effects via dual agonism at µ-opioid and adrenergic-α2 receptors.