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
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 anal...
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/12/4848 |
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| author | Ross van de Wetering Amy Ewald Susan Welsh Lindsay Kornberger Samuel E. Williamson Bryan D. McElroy Eduardo R. Butelman Thomas E. Prisinzano Bronwyn M. Kivell |
| author_facet | Ross van de Wetering Amy Ewald Susan Welsh Lindsay Kornberger Samuel E. Williamson Bryan D. McElroy Eduardo R. Butelman Thomas E. Prisinzano Bronwyn M. Kivell |
| author_sort | Ross van de Wetering |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T02:06:14Z |
| format | Article |
| id | doaj.art-54b17a5470e048c9ae4d03998c440fe7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T02:06:14Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-54b17a5470e048c9ae4d03998c440fe72023-11-18T11:51:11ZengMDPI AGMolecules1420-30492023-06-012812484810.3390/molecules28124848The 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 BehaviorsRoss van de Wetering0Amy Ewald1Susan Welsh2Lindsay Kornberger3Samuel E. Williamson4Bryan D. McElroy5Eduardo R. Butelman6Thomas E. Prisinzano7Bronwyn M. Kivell8School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New ZealandSchool of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New ZealandSchool of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New ZealandDepartment of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40506, USADepartment of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USALaboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USALaboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USADepartment of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40506, USASchool of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New ZealandKappa 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.https://www.mdpi.com/1420-3049/28/12/4848kappa opioid receptorsalvinorin Acocaineaddictionside effects |
| spellingShingle | Ross van de Wetering Amy Ewald Susan Welsh Lindsay Kornberger Samuel E. Williamson Bryan D. McElroy Eduardo R. Butelman Thomas E. Prisinzano Bronwyn M. Kivell 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 Molecules kappa opioid receptor salvinorin A cocaine addiction side effects |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | kappa opioid receptor salvinorin A cocaine addiction side effects |
| url | https://www.mdpi.com/1420-3049/28/12/4848 |
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