ORIGINAL INVESTIGATION
Effects of nalfurafine on the reinforcing, thermal antinociceptive,
and respiratory-depressant effects of oxycodone: modeling
an abuse-deterrent opioid analgesic in rats
E. Andrew Townsend
1,2
&
Jennifer E. Naylor
3
&
S. Stevens Negus
4
&
Shelley R. Edwards
5
&
Hina N. Qureshi
5
&
Hunter W. McLendon
6
&
Christopher R. McCurdy
7,8
&
Coco N. Kapanda
7
&
Jussara M. do Carmo
9
&
Fernanda S. da Silva
9
&
John E. Hall
9
&
Kenneth J. Sufka
10
&
Kevin B. Freeman
2
Received: 18 April 2017 /Accepted: 19 May 2017 / Published online: 31 May 2017
#
Springer-Verlag Berlin Heidelberg 2017
Abstract
Rationale Strategies to reduce the misuse of mu opioid ago-
nists are critically needed. Previous work has shown that kap-
pa 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 pro-
portions to be examined intravenously across procedures, a
progressive ratio (PR) self-administration procedure com-
pared 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 pro-
portions. Finally, the respiratory-depressant effects of equi-
antinociceptive doses of oxycodone, nalfurafine, and the mix-
tures were compared.
Results Nalfurafine decreased the reinforcing effects of oxy-
codone, 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 aug-
ment the thermal antinociceptive effects while reducing the
reinforcing and respiratory-depressant effects of oxycodone.
Keywords Abuse liability
.
Remitch
.
Plethysmography
* E. Andrew Townsend
s52drew@gmail.com
1
Graduate Program in Neuroscience, The University of Mississippi
Medical Center, Jackson, MS, USA
2
Department of Psychiatry and Human Behavior, The University of
Mississippi Medical Center, Jackson, MS, USA
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
Psychopharmacology (2017) 234:2597–2605
DOI 10.1007/s00213-017-4652-3
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