E Andrew Townsend1,2, Jennifer E Naylor3, S Stevens Negus4, Shelley R Edwards5, Hina N Qureshi5, Hunter W McLendon6, Christopher R McCurdy7,8, Coco N Kapanda7, Jussara M do Carmo9, Fernanda S da Silva9, John E Hall9, Kenneth J Sufka10, Kevin B Freeman11. 1. Graduate Program in Neuroscience, The University of Mississippi Medical Center, Jackson, MS, USA. s52drew@gmail.com. 2. Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, Jackson, MS, USA. s52drew@gmail.com. 3. National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA. 4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA. 5. Millsaps College, Jackson, MS, USA. 6. School of Medicine, The University of Mississippi Medical Center, Jackson, MS, USA. 7. Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, USA. 8. UF Translational Drug Development Core, Department of Medicinal Chemistry, School of Pharmacy, University of Florida, Gainesville, FL, USA. 9. Deprtment of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, MS, USA. 10. Department of Psychology, University of Mississippi, University, MS, USA. 11. Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, Jackson, MS, USA.
Abstract
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.
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.
Authors: C Austin Zamarripa; Jennifer E Naylor; Sally L Huskinson; E Andrew Townsend; Thomas E Prisinzano; Kevin B Freeman Journal: Psychopharmacology (Berl) Date: 2020-01-31 Impact factor: 4.530
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