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The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats

  • Takato Hiranita
  • Francisco Leon
  • Jasmine S. Felix
  • Luis F. Restrepo
  • Morgan E. Reeves
  • Anna E. Pennington
  • Samuel Obeng
  • Bonnie A. Avery
  • Christopher R. McCurdy
  • Lance R. McMahon
  • Jenny L. WilkersonEmail author
Original Investigation

Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Pain Kratom Analgesia Hot plate Opioid Rodent 

Abbreviations

AAALAC

Association for Assessment and Accreditation of Laboratory Animal Care

CL

Confidence limits

DEA

Drug Enforcement Administration

EtOAc

Ethyl acetate

FR

Fixed ratio

MPE

Maximum possible effect

NMR

Nuclear magnetic resonance

Notes

Acknowledgements

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.

Author’s contributions

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

Funding information

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.

Supplementary material

213_2019_5247_MOESM1_ESM.docx (199 kb)
ESM 1 (DOCX 198 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Takato Hiranita
    • 1
  • Francisco Leon
    • 2
  • Jasmine S. Felix
    • 1
  • Luis F. Restrepo
    • 1
  • Morgan E. Reeves
    • 1
  • Anna E. Pennington
    • 1
  • Samuel Obeng
    • 1
  • Bonnie A. Avery
    • 3
  • Christopher R. McCurdy
    • 2
  • Lance R. McMahon
    • 1
  • Jenny L. Wilkerson
    • 1
    Email author
  1. 1.Department of Pharmacodynamics, College of PharmacyUniversity of FloridaGainesvilleUSA
  2. 2.Department of Medicinal Chemistry, College of PharmacyUniversity of FloridaGainesvilleUSA
  3. 3.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA

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