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

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.

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…The acquisition in the males was consistent with that observed using similar procedures in a group of experimentally naïve adult males (Nguyen et al, 2019). Unfortunately the majority of rat oxycodone IVSA studies published so far have been in male rats (Austin Zamarripa et al, 2018;Blackwood et al, 2019;Bossert et al, 2018;Jordan et al, 2019;Leri and Burns, 2005;Mavrikaki et al, 2019;Nawarawong et al, 2018;Neelakantan et al, 2017;Nguyen et al, 2019;Nguyen, J. D. et al, 2018b;Pravetoni et al, 2014;Townsend et al, 2017;Wade et al, 2015;You et al, 2018;You et al, 2017); one exception was a study in pregnant rats (Vassoler et al, 2018). Interestingly, when female animals were evaluated on a fentanyl dose substitution under an FR procedure, the THC exposed rats self-administered more drug at the lowest dose (Figure 9).…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…Our study is in line with growing research into the development of biased KOP-r ligands for anti-addictive compounds [Maillet et al, 2015;White et al, 2015;Brust et al, 2016;Townsend et al, 2017].…”

“…Recently, there is rapidly growing research into the identification of functionally selective (biased) KOP-r full agonists or partial agonists for the development of anti-addictive compounds [Maillet et al, 2015;Simonson et al, 2015;White et al, 2015;Brust et al, 2016;Schattauer et al, 2017;Townsend et al, 2017;Zhou et al, 2017a]. For a good example, Mesyl Salvinorin B (MSB), an analogue of salvinorin A, is a potent KOP-r full agonist with fewer side effects (sedation and dysphoria) compared to other "classic" KOP-r agonists [Simonson et al, 2015;Zhou et al, 2017a].…”

Role of mu, but not delta or kappa, opioid receptors in context‐induced reinstatement of oxycodone seeking

“…However, in light of the current prescription opioid epidemic, we recently changed our focus to studying relapse to oxycodone, a prototypical prescription opioid drug that is widely used for pain management (Van Zee, 2009;Yaksh & Wallace, 2011). We also chose to study oxycodone because compared to heroin (Wise, 1989;Koob, 1992;Badiani et al, 2011;Bossert et al, 2013), there are very few published studies on oxycodone self-administration and relapse/reinstatement (Leri & Burns, 2005;Campbell et al, 2012;Pravetoni et al, 2014;Secci et al, 2016;Neelakantan et al, 2017;Townsend et al, 2017;You et al, 2017). Human and rodent binding studies show that oxycodone is a preferential mu opioid receptor (MOR) agonist (Lalovic et al, 2006;Peckham & Traynor, 2006) with lower affinity to MOR than morphine (Lalovic et al, 2006;Peckham & Traynor, 2006); there is also evidence that oxycodone binds to the kappa opioid receptor (KOR) (Nielsen et al, 2007).…”