Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.

Bronwyn Kivell,Amy Shepherd,Nitin Kumar,Thomas Prisinzano,Rachel Crowley,Andrew Biggerstaff,Susan Welsh,Aimee Culverhouse,Kelly Paton,Aashish Morani

doi:10.3390/molecules23102602

Bronwyn Kivell, Amy Shepherd + Show 8 more

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https://doi.org/10.3390/molecules23102602

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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.

Highlights

Drug addiction is a relapsing, compulsive disorder characterized by a lack of control in drug intake even when adverse consequences are apparent [1,2]
The results show that Mesyl Sal B exerts only partial effects compared to Salvinorin A (Sal A) and U50488 (Figure 3), which is in contrast to the results from in vitro cellular assays showing that U50488, Sal A, and Mesyl Sal B are all full agonists at the kappa opioid receptors (KOPr) [41,48]
The psychoactive natural product Sal A is a potent and selective KOPr agonist isolated from the plant Salvia divinorum [28,29]

Summary

Introduction

Drug addiction is a relapsing, compulsive disorder characterized by a lack of control in drug intake even when adverse consequences are apparent [1,2] Psychostimulants, such as cocaine, are widely abused and currently, there are no Food and Drug Administration (FDA) approved treatments for psychostimulant addiction. Molecules 2018, 23, 2602 cocaine-enhanced locomotion [5,6], behavioral sensitization to cocaine [7,8], and the reinstatement of extinguished cocaine-seeking [9,10]. These effects of KOPr agonists can be attributed to their ability to decrease dopamine levels in the nucleus accumbens [11,12,13]. KOPr activation in the ventral tegmental area decreases dopamine levels in the medial prefrontal cortex [15]

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