Differential tolerance and cross-tolerance to repeated daily injections of mu and kappa opioid agonists in the rat.

This study was designed to compare the development of tolerance to the effects of morphine and ethylketocyclazocine ( EKC ) on EEG, EEG power spectra and behavior and to assess any cross-tolerance. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle EMG recording electrodes and with permanent cannulae in the external jugular vein. In non-tolerant rats, 10 mg/kg (i.v.) injections of morphine and of ethylketocyclazocine produced biphasic EEG and behavioral profiles lasting for 3 and 2 hr , respectively. In both cases, a stuporous phase, associated with high-voltage cortical EEG bursts, was followed by a hyperactive phase, associated with low-voltage desynchronized EEG. However, power spectra derived from epochs of EEG bursting produced by morphine and ethylketocyclazocine were qualitatively different. One group of rats was then given a series of automatic, intravenous injections of morphine, while a second group received ethylketocyclazocine. Following chronic treatment, the duration of the biphasic EEG and behavioral profiles induced by morphine and ethylketocyclazocine were both significantly reduced. In both cases, the intensity of EEG bursting was also reduced as reflected by significant quantitative reductions in EEG power spectral densities. In assessments of cross-tolerance, ethylketocyclazocine tolerant rats were found to be cross-tolerant to the effects of morphine. However, no cross-tolerance to the effects of ethylketocyclazocine in morphine-tolerant rats was observed. These data contribute to a further understanding of the relative heterogeneity of mu and kappa receptor populations and to the differential pharmacodynamics of morphine and ethylketocyclazocine.