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Kratom ( Mitragyna speciosa ), containing the primary alkaloid mitragynine, has emerged as an alternative self-treatment for opioid use disorder. Mitragynine binds numerous receptor types, including opioid receptors, which are known to modulate food consumption. However, the ability of acute mitragynine to modulate food consumption remains unknown. The current study assessed the effects of acute mitragynine or morphine administration on unconditioned food and water intake in 16 Sprague-Dawley rats. Food and water intake changes were monitored in response to morphine, mitragynine (1.78-56 mg/kg ip), saline, or vehicle controls for 12 h, starting at the onset of the dark cycle. Naltrexone pretreatment was used to examine pharmacological specificity. Both morphine and mitragynine demonstrated a biphasic food intake dose-effect, with low doses (5.6 mg/kg) increasing and high doses (56 mg/kg) decreasing food intake. All morphine doses reduced water intake; however, only the highest dose of mitragynine (56 mg/kg) reduced water intake. Naltrexone attenuated both stimulatory and inhibitory effects of morphine on food intake, but only the stimulatory effect of mitragynine. In conclusion, low doses of mitragynine stimulate food intake via opioid-related pathways, while high doses likely recruit other targets. NEW & NOTEWORTHY This study reveals that morphine and the kratom alkaloid mitragynine produce dose-dependent effects on feeding in rats. Low doses stimulate food intake via opioid pathways, while high doses decrease consumption through nonopioid mechanisms. Morphine potently suppresses water intake at all doses, whereas only high doses of mitragynine reduce drinking. These findings provide novel insights into the complex opioid and nonopioid mechanisms underlying the effects of mitragynine on ingestive behaviors.

Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at μ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α 2 receptors (Aα 2 Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα 2 R antagonist ([ 3 H]RX821002) from human Aα 2A Rs in vitro with lower affinity (K i  = 1260 nM) than the agonists (-)-epinephrine (K i  = 263 nM) or lofexidine (K i  = 7.42 nM). Mitragynine did not significantly stimulate [ 35 S]GTPγS binding at Aα 2A Rs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα 2 R agonist-like effect. Both α 2 R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα 2 R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα 2 R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα 2 R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα 2 R agonist, although its failure to induce hypothermia or stimulate [ 35 S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα 2 R agonist., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Opioids represent the most extensive category of abused substances in the United States, and the number of fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration of naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal and induce severe side effects. There is a pressing demand for opioid antagonists free of opioid withdrawal effects. In our laboratory, we have identified a compound with affinity to mu, delta, and kappa opioid receptors in the range of 150-250 nM. This blood-brain barrier (BBB)-permeant compound was metabolically stable in vitro and in vivo . Our in vivo work demonstrated that 1-10 mg/kg intraperitoneal administration of our compound produces moderate efficacy in antagonizing morphine-induced antiallodynia effects in the chemotherapy-induced peripheral neuropathy (CIPN) model. The treatment was well-tolerated and did not cause behavioral changes. We have observed a fast elimination rate of this metabolically stable molecule. Furthermore, no organ toxicity was observed during the chronic administration of the compound over a 14-day period. Overall, we report a novel functional opioid antagonist holds promise for developing an opioid withdrawal therapeutic., Competing Interests: The authors declare the following competing financial interest(s): Compounds described herein are the subject of published patent applications; U.S. Pat. Appl. Publ. (2020), US 2020/0131183 A1., (© 2024 American Chemical Society.)

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ -opioid receptors (MORs) and adrenergic- α 2 receptors (A α 2 Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). A α 2 R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the A α 2 R antagonist yohimbine. Hypothermia only resulted from reference A α 2 R agonists. The rate-deceasing and hypothermic effects of reference A α 2 R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of A α 2 R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference A α 2 R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with A α 2 R and MOR agonists. When combined with A α 2 R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT: Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α 2 receptor (Aα 2 R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα 2 R and MOR agonists. When combined with Aα 2 R agonists, mitragynine could also produce hypothermic synergism., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Synthetic cathinones gained initial popularity on the illicit drug market as a result of attempts to evade legal restrictions on other commonly abused psychostimulants. A body of published research has determined that the psychopharmacology of the synthetic cathinone 3, 4-methylenedioxypyrovalerone (MDPV) is comparable to cocaine and methamphetamine (METH). Few preclinical studies have systematically investigated concurrent use of synthetic cathinones with other psychostimulant drugs. The present study utilized conditioned place preference (CPP), a rodent model of conditioned drug reward, to evaluate the effects of concurrent treatment with MDPV and METH. Male (N = 72) and female (N = 105) Sprague-Dawley rats underwent a two-compartment biased CPP procedure, with one trial per day for eight consecutive days. Subjects were randomly assigned to the following treatment groups: saline, METH (1 mg/kg), MDPV (1, 3.2, 5.6 mg/kg) or a mixture consisting of METH (1 mg/kg) and MDPV (1, 3.2, 5.6 mg/kg). All treatments increased locomotor activity during drug conditioning trials, and most treatments produced higher activity increases in females compared to males. Although the level of CPP established by MDPV and MDPV + METH mixtures varied between males and females, sex differences were not statistically significant. Although none of the MDPV+METH mixtures produced stronger CPP than either substance alone, some mixtures of MDPV and METH produced higher increases in locomotor activity compared to either drug alone. Further studies with higher doses may be warranted to determine if concurrent use of MDPV and METH pose an enhanced risk for abuse., (Copyright © 2020 Elsevier Inc. All rights reserved.)