Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids

Rationale: Discriminative stimulus effects of mu opioids vary systematicall y as a function of training dose. Differences among training doses may aris e from multiple mechanisms. Objectives: In vivo apparent pA(2) analyses wer e used to examine the contributions of opioid mechanisms to stimulus contro l by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as d iscriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in v ivo apparent pA(2) analyses were used to evaluate receptor mechanisms of st imulus control. Results: Fentanyl, etonitazene, methadone, and morphine evo ked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA(2) values of 7.6 in the low-d ose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine a ntagonized the stimulus and rate-altering effects of fentanyl with apparent pA(2) values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu o pioid selectivity of stimulus control bur altered the intensity of the tran sduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opio ids would evoke or antagonize fentanyl generalization.