Bidirectional cross-tolerance between methadone (Mu)- and EKC (kappa)-tolerant rats

We have previously reported on unidirectional cross-tolerance between morphine and methadone (Toxicol. Appl. Pharmacol., 45, 1978) and between morphine and ethylketocyclazocine (EKC) (Neuropharmacology, 23, 1984). In these studies morphine-tolerant rats were found to be non cross-tolerant to methadone or EKC, but methadone- and EKC-tolerant rats were cross-tolerant to morphine. In the present study, female adult Sprague-Dawley rats were made tolerant to methadone by a series of automatic i.v. injections reaching a dose of 2 mg/kg/1.5 hrs. Another group of rats was similarly made tolerant to EKC reaching a dose of 4 mg/kg/hr. In control rats methadone (2 mg/kg, i.v.) produced a biphasic EEG and behavioral response consisting of 30-60 min of depression followed by 30-60 min of arousal. Also, in control rats EKC (5 mg/kg, i.v.) produced a similar biphasic EEG and behavioral response. On the other hand, the methadone-tolerant rats were found to be cross-tolerant to the EEG and behavioral effects of EKC, and, similarly, EKC-tolerant rats were found to be cross-tolerant to those of methadone. The present results together with those reported earlier may not be directly related to opioid selectivity. Differential physicochemical properties of these opioids play a role in the phenomenon of cross-tolerance.