Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats

• Published in: Psychopharmacology 2017-09, Vol.234 (17), p.2597-2605
• Main Authors: Townsend, E. Andrew, Naylor, Jennifer E., Negus, S. Stevens, Edwards, Shelley R., Qureshi, Hina N., McLendon, Hunter W., McCurdy, Christopher R., Kapanda, Coco N., do Carmo, Jussara M., da Silva, Fernanda S., Hall, John E., Sufka, Kenneth J., Freeman, Kevin B.
• Format: Article
• Language: English
• Subjects: Abuse; Analgesics - pharmacology; Analgesics, Opioid - pharmacology; Animals; Antipruritics; Biomedical and Life Sciences; Biomedicine; Dose-Response Relationship, Drug; Drug abuse; Drug interactions; Male; Models, Animal; Morphinans - pharmacology; Narcotics; Neurosciences; Nociception - drug effects; Opioid abuse; Opioid receptors (type kappa); Opioid receptors (type mu); Opioid-Related Disorders - prevention & control; Original Investigation; Oxycodone; Oxycodone - pharmacology; Pain perception; Patient outcomes; Pharmaceutical research; Pharmacology/Toxicology; Prevention; Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Reinforcement (Psychology); Respiration - drug effects; Rodents; Self Administration; Side effects; Spiro Compounds - pharmacology
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-017-4652-3

Rationale Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. Objectives The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. Methods To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Results Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. Conclusions These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.