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

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

  • Molecules. 2018 Oct 11;23(10):2602. doi: 10.3390/molecules23102602.
Bronwyn M Kivell 1,  Kelly F Paton 2,  Nitin Kumar 3,  Aashish S Morani 4,  Aimee Culverhouse 5,  Amy Shepherd 6,  Susan A Welsh 7,  Andrew Biggerstaff 8,  Rachel S Crowley 9,  Thomas E Prisinzano 10
Affiliations

Affiliations

  • 1 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. bronwyn.kivell@vuw.ac.nz.
  • 2 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. kelly.paton@vuw.ac.nz.
  • 3 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. nitin23784@yahoo.com.
  • 4 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. aashu110@gmail.com.
  • 5 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. aimee.culverhouse@vuw.ac.nz.
  • 6 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. shepheamy@gmail.com.
  • 7 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. midgii@gmail.com.
  • 8 School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand. Andy.Biggerstaff@vuw.ac.nz.
  • 9 Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 6604, USA. crowleyrachels@outlook.com.
  • 10 Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 6604, USA. prisinza@ku.edu.
PMID: 30314288 DOI: 10.3390/molecules23102602
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.

Keywords

Salvinorin A; addiction; behavioral pharmacology; behavioral sensitization; conditioned taste aversion; depression; drug abuse; forced swim test; kappa opioid; locomotion.

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