Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.
Bronwyn M Kivell, Kelly F Paton, Nitin Kumar, Aashish S Morani, Aimee Culverhouse, Amy Shepherd, Susan A Welsh, Andrew Biggerstaff, Rachel S Crowley, Thomas E Prisinzano
Molecules (Basel, Switzerland) October 11, 2018 DOI: 10.3390/molecules23102602 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male Sprague Dawley rats and male B6.SJL mice |
| Intervention | Mesyl Sal B |
| Dose | 0.3 mg/kg |
| Measures | conditioned taste aversion, conditioned place aversion, forced swim test, elevated plus maze, novel object recognition, warm-water tail withdrawal, intraplantar formaldehyde assay, rotarod performance task |
| Topics | Addiction Depression Salvia divinorum |
| Keywords | Behavioral pharmacology Behavioral sensitization Conditioned taste aversion Drug abuse Forced swim test Kappa opioid Locomotion |
| Citations | 45 |
| Key points | Mesyl Sal B attenuates cocaine-induced hyperactivity and behavioral sensitization without producing aversion, sedation, anxiety, or learning and memory impairment, but it induces pro-depressive effects and has limited antinociceptive potency compared to Salvinorin A. |
Abstract
The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.