The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats

C. Austin Zamarripa, Tanya Pareek, Hayley M. Schrock, Thomas E. Prisinzano, Bruce E. Blough, Kenneth J. Sufka, Kevin B. Freeman

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Rationale: Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists. Objectives: The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone. Methods: In the self-administration study, male Sprague–Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488 h (0.032-0.32 mg/kg/inj), nalfurafine (0.00032–0.0032 mg/kg/inj), or triazole 1.1 (0.32–1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6 mg/kg), U50,488h (1.0-18.0 mg/kg), nalfurafine (0.01-1.0 mg/kg), or triazole 1.1 (3.2-32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation. Results: All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures. Conclusion: This study demonstrates that triazole 1.1 reduces oxycodone’s reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1’s mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.

Original languageEnglish
Pages (from-to)3463-3476
Number of pages14
Issue number12
StatePublished - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.


  • Hot plate
  • Kappa agonist
  • Nalfurafine
  • Oxycodone
  • Self-administration
  • Thermal antinociception
  • Triazole 1.1
  • U50,488 h

ASJC Scopus subject areas

  • Pharmacology


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