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Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice

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Abstract

Background

For many chemotherapy patients peripheral neuropathy is a debilitating side effect. Mitragyna speciosa (kratom) contains the alkaloid mitragynine (MG), which produces analgesia in multiple preclinical pain models. In humans, anecdotal reports suggest cannabidiol (CBD) may enhance kratom-related analgesia. We examined the interactive activity of MG and CBD in a mouse chemotherapy-induced peripheral neuropathy (CIPN) model. We also examined MG + CBD in acute antinociception and schedule-controlled responding assays, as well as examined underlying receptor mechanisms.

Methods

Male and female C57BL/6J mice received a cycle of intraperitoneal (ip) paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN allodynia. In paclitaxel-naïve mice, schedule-controlled responding for food was conducted under a fixed ratio (FR)-10, and hot plate antinociception was examined.

Results

MG dose-relatedly attenuated CIPN allodynia (ED50 102.96 mg/kg, ip), reduced schedule-controlled responding (ED50 46.04 mg/kg, ip), and produced antinociception (ED50 68.83 mg/kg, ip). CBD attenuated allodynia (ED50 85.14 mg/kg, ip) but did not decrease schedule-controlled responding or produce antinociception. Isobolographic analysis revealed 1:1, 3:1 MG + CBD mixture ratios additively attenuated CIPN allodynia. All combinations decreased schedule-controlled responding and produced antinociception. WAY-100635 (serotonin 5-HT1A receptor antagonist) pretreatment (0.01 mg/kg, ip) antagonized CBD anti-allodynia. Naltrexone (pan opioid receptor antagonist) pretreatment (0.032 mg/kg, ip) antagonized MG anti-allodynia and acute antinociception but produced no change in MG-induced decreased schedule-controlled behavior. Yohimbine (α2 receptor antagonist) pretreatment (3.2 mg/kg, ip) antagonized MG anti-allodynia and produced no change in MG-induced acute antinociception or decreased schedule-controlled behavior.

Conclusions

Although more optimization is needed, these data suggest CBD combined with MG may be useful as a novel CIPN therapeutic.

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Data availability

The datasets generated and analyzed during this study are available in the Open Science Framework repository (https://doi.org/10.17605/OSF.IO/5TZK3) and are available from the corresponding author upon reasonable request.

Abbreviations

α2 :

α2-Adrenergic

% MPE:

Percentage maximum possible effect

5-HT1A :

Serotonin 1A

7-OH-MG:

7-Hydroxymitragynine

ANOVA:

Analysis of variance

CBD:

Cannabidiol

CIPN:

Chemotherapy-induced peripheral neuropathy

FR:

Fixed ratio

ip :

Intraperitoneal

MG:

Mitragynine

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Funding

This work was supported by the National Institute on Drug Abuse [Grant DA25267, DA48353] (CRM and LRM) and funding from the Florida Consortium for Medical Marijuana Clinical Outcomes Research (JLW). The authors would like to thank Ms. Danielle M. Sevier and Ms. Samantha N. Hart at the College of Pharmacy, University of Florida, for administrative assistance.

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Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Yuma T. Ortiz, Lance R. McMahon & Jenny L. Wilkerson

  2. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter., Amarillo, TX, 79106, USA

    Yuma T. Ortiz, Lance R. McMahon & Jenny L. Wilkerson

  3. College of Pharmacy, University of Florida, Gainesville, FL, USA

    Joshua A. Bilbrey, Jasmine S. Felix & Erik A. Kienegger

  4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Marco Mottinelli, Sushobhan Mukhopadhyay & Christopher R. McCurdy

  5. Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, MA, USA

    Marco Mottinelli

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  1. Yuma T. Ortiz
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Contributions

Participated in research design: YTO, LR, JLW. Conducted experiments: JAB, JSF, EAK, YTO. Contributed new reagents or analytic tools: MM, SM and CRM. Performed data analysis: JSF, YTO, JLW. Wrote or contributed to the writing of the manuscript: YTO, EAK, MM, LRM, JLW.

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Correspondence to Jenny L. Wilkerson.

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Ortiz, Y.T., Bilbrey, J.A., Felix, J.S. et al. Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice. Pharmacol. Rep 75, 937–950 (2023). https://doi.org/10.1007/s43440-023-00498-w

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