Bidirectional cross-tolerance between methadone (mu)- and ethylketocyclazocine (kappa)-tolerant rats

Our laboratory previously reported on unidirectional cross-tolerance between morphine and methadone, both mu opioid agonists, and between morphine and ethylketocyclazocine (EKC), the latter being a relatively selective kappa opioid agonist. Morphine-tolerant rats were found to be non-cross-tolerant to methadone and EKC, but methadone- and EKC-tolerant rats were cross tolerant to morphine. In the present study, we characterized the cross-tolerance between methadone and EKC. A group of female adult Sprague-Dawley rats was made tolerant to methadone by a series of automatic i.v. injections ranging from 0.25 mg/kg per 2 h on the first day to 2.0 mg/kg per 1.5 h on the ninth day. Another group of rats was similarly made tolerant to EKC with doses ranging from 0.5 mg/kg per 2 h on the first day to 4 mg/kg per h on the ninth day. Relatively similar degrees of tolerance development to the EEG and behavioral effects of methadone and EKC were reflected by decreases in durations of action and decreases in opioid-induced EEG power spectral changes. 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. Thus, a bidirectional cross-tolerance between a mu and a kappa agonist was demonstrated. The present results together with those reported earlier indicate that cross-tolerance may not be directly related to the receptor selectivity of the opioids. It is possible that differential physicochemical properties of these opioids may play a more decisive role in the phenomenon of cross-tolerance.