Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities.
Adam W Keasling, Pankaj Pandey, Robert J Doerksen, Gustavo R. Pedrino, Elson A Costa, Luiz C Da Cunha, Jordan K Zjawiony, James O Fajemiroye
Journal of Psychopharmacology July 2019 DOI: 10.1177/0269881119849821 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Salvindolin naloxone naloxonazine nor-binaltorphimine WAY100635 |
| Measures | acetic-acid-induced writhing test, formalin test, hot plate test, forced swim test, tail suspension test, open field test |
| Topics | Salvia divinorum |
| Keywords | Affinity Anti-depressive like Antinociception In vitro In vivo Ligands Molecular docking Opioid receptors Protein modeling Salvindolin Semi-synthesis |
| Key findings | Salvindolin, a semisynthetic analog of salvinorin A, shows 100-fold preference for mu over kappa opioid receptors and produces antinociceptive and antidepressant-like effects in mice without locomotor incoordination. These effects are mediated through mu opioid and serotonin 1A receptors, suggesting potential as an analgesic and/or antidepressant drug candidate. |
Abstract
Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects. In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities. Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins. Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin. By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
Comparable studies
Other preclinical and animal studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Mice | 2005 | Experimental study | |
| Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents Male Sprague-Dawley rats and male Albino Swiss mice | 2009 | Experimental study | |
| Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Wistar rats | 2008 | Experimental study | |
| Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Rats | 2010 | Experimental study | |
| The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Rhesus monkeys | 2004 | Experimental study | n = 3 |
Citations in the library
Cited by 5
- Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects Pharmaceuticals February 3, 2021
- The translational potential of salvinorin A: systematic review and meta-analysis of preclinical studies. Translational Psychiatry October 10, 2025
- Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects. Fitoterapia June 1, 2023
- Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor Preprints.org November 1, 2022
- A Protecting-Group-Free Synthesis of (-)-Salvinorin A. Chemistry - A European Journal May 20, 2021
Cites 18
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Journal of Pharmacology and Experimental Therapeutics March 1, 2004
- Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide F1000Research May 24, 2018
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and 13 more in the library