Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors.
Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan’s relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 μg/kg/injection) and heroin (7.5, 15, 25 μg/kg/injection) were comparators.
All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend (p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significantly lower than all heroin doses. The numbers of self-administered samidorphan and naltrexone injections/session on fixed ratio-5 were not significantly different from one another. The mean inter-injection intervals for heroin were significantly shorter than for saline, whereas those of samidorphan and naltrexone were not. Progressive ratio break-points for samidorphan and naltrexone were not different from saline except for the highest dose of samidorphan. In addition, the progressive ratio break-points for samidorphan were not significantly different from those of naltrexone and were significantly lower than heroin. The samidorphan unit-doses evaluated in self-administration yielded plasma concentrations ranging between 25-109% and 10-45% of the maximum concentration values in humans.
Overall, the profiles of samidorphan and naltrexone, which has no abuse liability, were similar in this model.
For more details or information on how we can support your project please complete the contact form.