The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors.
Ross Van de Wetering, Amy W M Ewald, Susan A Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D McElroy, Eduardo R Butelman, Thomas E Prisinzano, Bronwyn M Kivell
Molecules June 19, 2023 DOI: 10.3390/molecules28124848 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Sprague Dawley rats, B6-SJL mice, non-human primates, and HEK-293 cells |
| Interventions | 16-bromo salvinorin A (16-BrSalA) cocaine |
| Measures | elevated plus maze, light-dark test, forced swim test, sucrose self-administration, novel object recognition, progressive ratio schedule |
| Topics | Addiction Anxiety Salvia divinorum |
| Keywords | Animals Humans Mice Rats, sprague-dawley Diterpenes, clerodane Cocaine Receptors, opioid, kappa Reward Locomotion Hek293 cells Side effects Kappa opioid receptor |
| Key points | 16-BrSalA dose-dependently reduced cocaine-primed reinstatement of drug-seeking and cocaine-induced hyperactivity in a kappa opioid receptor-dependent manner, but did not alter progressive-ratio responding for cocaine. It showed fewer side effects than salvinorin A on several behavioral measures, though it still produced conditioned aversion, and it increased dopamine transporter activity and ERK1/2 and p38 signaling. |
Abstract
Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light-dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects.
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
Cites 23
- Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Journal of Medicinal Chemistry December 26, 2014
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage July 1, 2008
- Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats. Pharmacology, Biochemistry, and Behavior December 1, 2009
- Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates. Synapse December 1, 2005
and 18 more in the library