The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys

Sally L. Huskinson, Donna M. Platt, C. Austin Zamarripa, Kristen Dunaway, Morgan Brasfield, Thomas E. Prisinzano, Bruce E. Blough, Kevin B. Freeman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01–0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.32–1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01–0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0–56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.

Original languageEnglish
Article number173394
JournalPharmacology Biochemistry and Behavior
Volume217
DOIs
StatePublished - Jun 2022

Bibliographical note

Funding Information:
The authors would like to thank Josh Woods, Kandace Farmer, Jessica Howard, Jemma Cook, Lais Berro, Tanya Pareek, and Zachary Smith for their technical assistance. Morgan Brasfield is now at William Carey University in Hattiesburg, MS 39401 and C. Austin Zamarripa is now at Johns Hopkins University School of Medicine in Baltimore, MD 21205. This work was supported by the National Institute on Drug Abuse [ DA039167 to K.B.F.; DA018151 to T.E.P; DA045011 to S.L.H; DA048586 to C.A.Z.] and the National Institute on Alcohol Abuse and Alcoholism [ AA029023 to D.M.P.].

Funding Information:
The authors would like to thank Josh Woods, Kandace Farmer, Jessica Howard, Jemma Cook, Lais Berro, Tanya Pareek, and Zachary Smith for their technical assistance. Morgan Brasfield is now at William Carey University in Hattiesburg, MS 39401 and C. Austin Zamarripa is now at Johns Hopkins University School of Medicine in Baltimore, MD 21205. This work was supported by the National Institute on Drug Abuse [DA039167 to K.B.F.; DA018151 to T.E.P; DA045011 to S.L.H; DA048586 to C.A.Z.] and the National Institute on Alcohol Abuse and Alcoholism [AA029023 to D.M.P.].

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Kappa-opioid receptor
  • Mu-opioid receptor
  • Observable behavior
  • Rhesus monkey

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

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