The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats
Mitragyna speciosa (kratom) may hold promise as both an analgesic and treatment for opioid use disorder. Mitragynine, its primary alkaloid constituent, is an opioid receptor ligand. However, the extent to which the in vivo effects of mitragynine are mediated by opioid receptors, or whether mitragynine interacts with other opioid agonists, is not fully established.
The effects of mitragynine and the prototypical opioid agonist morphine were compared for their capacity to decrease operant responding for food delivery, and to increase response latency to a thermal stimulus.
Male and female Sprague-Dawley rats responded under a multiple cycle fixed ratio 10 schedule of food delivery and were tested on a hot plate (52 °C) immediately after each cycle. Morphine and mitragynine were administered alone, in combination with each other, and in combination with the opioid antagonist naltrexone.
Morphine and mitragynine dose-dependently decreased schedule-controlled responding; the ED50 values were 7.3 and 31.5 mg/kg, respectively. Both drugs increased thermal antinociception; the ED50 value for morphine was 18.3. Further, doses of naltrexone that antagonized morphine did not antagonize mitragynine. Mitragynine (17.8 mg/kg) did not alter the rate-decreasing or antinociceptive effects of morphine.
The antinociceptive effects of mitragynine and morphine occur at doses larger than those that disrupt learned behavior. Opioid receptors do not appear to mediate the disruptive effects of mitragynine on learned behavior. Mitragynine had lesser antinociceptive effects than morphine, and these did not appear to be mediated by opioid receptors. The pharmacology of mitragynine includes a substantial non-opioid mechanism.
KeywordsPain Kratom Analgesia Hot plate Opioid Rodent
Association for Assessment and Accreditation of Laboratory Animal Care
Drug Enforcement Administration
Maximum possible effect
Nuclear magnetic resonance
We humbly dedicate this work in memory of our friend and colleague, Dr. Bonnie A. Avery. She had an invaluable influence on many students and colleagues, and her contributions in the areas of pharmacokinetics, analytical chemistry, and drug metabolism will remain a driving force in better understanding novel, potential drug candidates as well as complex natural product mixtures. Her research interests also spanned into the complex pharmacophore of Mitragyna speciosa. We will always be grateful for her unparalleled support and guidance as well as the inspiration to live by the qualities and ideals she promoted through her boundless courage, hard work, dedication, and loyalty. She will be dearly missed.
The authors would like to thank Dr. Hannah Harris, Ms. Lisa Wilson, and Ms. Ariana Brice for their technical assistance.
Participated in research design: Wilkerson, Hiranita, Avery, McMahon
Conducted experiments: Felix, Restrepo, Obeng, Pennington, Reeves
Contributed new reagents or analytic tools: Leon, McCurdy
Performed data analysis: Wilkerson, Hiranita, McMahon
Wrote or contributed to the writing of the manuscript: Wilkerson, Hiranita, Leon, McMahon
Research was supported by NIH grants DA25267 and DA48353.
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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