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Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: possible cannabinoid receptor involvement

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Abstract

Pain is one of the most common reasons to seek medical attention, and chronic pain is a worldwide epidemic. Anecdotal reports suggest cannabis may be an effective analgesic. As cannabis contains the terpenes α-terpineol, β-caryophyllene, and γ-terpinene, we hypothesized these terpenes would produce analgesia in a mouse model of neuropathic pain. We used the chronic constriction injury of the sciatic nerve mouse model, which produces mechanical allodynia, assessed via the von Frey assay, as well as thermal hyperalgesia assessed via the hotplate assay. Compounds were further assessed in tests of locomotor activity, hypothermia, and acute antinociception. Each terpene produced dose-related reversal of mechanical allodynia and thermal hyperalgesia. Thermal hyperalgesia displayed higher sensitivity to the effects of each terpene than mechanical allodynia, and the rank order potency of the terpenes was α-terpineol > β-caryophyllene > γ-terpinene. To examine the involvement of cannabinoid receptors, further tests were conducted in mice lacking either functional cannabinoid type 1 receptors (CB1R (−/−)) or cannabinoid type 2 receptors (CB2R (−/−)). Compared to wild type mice, CB1R (−/−) mice treated with α-terpineol displayed a 2.91-fold decrease in potency to reverse mechanical allodynia; in CB2R (−/−) mice, the potency of α-terpineol was decreased 11.73-fold. The potency of β-caryophyllene to reverse mechanical allodynia decreased 1.80-fold in CB2R (−/−) mice. Each terpene produced a subset of effects in tests of locomotor activity, hypothermia, and acute antinociception. These findings suggest α-terpineol, β-caryophyllene, and γ-terpinene may have differential cannabinoid receptor activity and a pharmacological profile that may yield new efficacious analgesics.

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Abbreviations

BL:

baseline

CB1R:

cannabinoid type 1 receptor

CB2R:

cannabinoid type 2 receptor

CCI:

chronic constriction injury

CL:

confidence limits

ED:

effective dose

iNOS:

inducible nitric oxide synthase

i.p.:

intraperitoneal

% MPE:

percent maximum possible effect

NF-κβ:

nuclear factor-kappa beta

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Funding

This work was supported by the National Institute on Drug Abuse DA25267 and DA48353 (LRM) and funding from the Florida Consortium for Medical Marijuana Clinical Outcomes Research (JLW).

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Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University of Florida, P.O. Box 100487, Gainesville, FL, USA

    Joshua A. Bilbrey, Yuma T. Ortiz, Jasmine S. Felix, Lance R. McMahon & Jenny L. Wilkerson

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  1. Joshua A. Bilbrey
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  2. Yuma T. Ortiz
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  3. Jasmine S. Felix
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  4. Lance R. McMahon
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  5. Jenny L. Wilkerson
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Contributions

Participated in research design: McMahon and Wilkerson. Conducted experiments: Bilbrey, Felix, and Ortiz. Performed data analysis: Felix, Ortiz, and Wilkerson. Wrote or contributed to the writing of the manuscript: Bilbrey, McMahon, and Wilkerson.

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Correspondence to Jenny L. Wilkerson.

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Bilbrey, J.A., Ortiz, Y.T., Felix, J.S. et al. Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: possible cannabinoid receptor involvement. Psychopharmacology 239, 1475–1486 (2022). https://doi.org/10.1007/s00213-021-06031-2

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