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Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents

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Abstract

Rationale

Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.

Objectives

This study represents a systematic examination of this hypothesis.

Methods

Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB1 receptor radioligand and [35S]GTPγS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.

Results

Salvinorin A did not bind to nor activate CB1 receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB1 receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [35S]GTPγS assay. Salvinorin A did not substitute for Δ9-tetrahydrocannabinol (THC) in mice trained to discriminate THC.

Conclusions

These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.

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Acknowledgments

This research is supported by National Institutes of Health/National Institute on Drug Abuse grant DA-03672.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA, 23298-0613, USA

    D. Matthew Walentiny, Robert E. Vann, Jonathan A. Warner & Lindsey S. King

  2. Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC, 27709-2194, USA

    Herbert H. Seltzman, Charles E. Twine Jr., Brian F. Thomas & F. Ivy Carroll

  3. Center for Pharmacology and Toxicology, Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA

    Hernán A. Navarro, Anne F. Gilliam, Brian P. Gilmour & Jenny L. Wiley

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  1. D. Matthew Walentiny
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  2. Robert E. Vann
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  12. Jenny L. Wiley
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Correspondence to Jenny L. Wiley.

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Walentiny, D.M., Vann, R.E., Warner, J.A. et al. Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents. Psychopharmacology 210, 275–284 (2010). https://doi.org/10.1007/s00213-010-1827-6

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  • DOI: https://doi.org/10.1007/s00213-010-1827-6

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