Morphine-induced regional and dose-response differences in multiple-unit activity in rabbits

In each of 14 rabbits, EEG and multiple-unit activity were recorded from 14 brain areas which had been suggested in the literature as primary target sites of opiate action. Each rabbit received intraperitoneal injections of 5, 15, 0 (saline) and 25 mg/kg of morphine sulphate, in that order, with at least one week between injections. This sequence was repeated in a cross-over design to permit testing for tolerance. Experiments were performed with rabbits induced into the Immobility Reflex to produce a relatively stable artifact-free electrographic activity with minimal influence from behavioral feedback and other variables. EEG recordings disclosed a dose-related decrease in the incidence of theta rhythm; no evidence for tolerance development was evident. Subjective evaluation of tracings from all areas did not disclose any drug-related regional differences. Quantitative analysis of multiple unit activity revealed only a mild positive correlation between percent time theta and change in multiple unit activity (only for a few brain areas and usually at the highest dose). An unexpected, comparatively mild change in multiple unit activity in the caudate nucleus and the periaqueductal grey may have resulted from the special features of this experimental design: the focus on the immediate post-injection period and on spontaneous, rather than evoked, electrographic activity. Results in certain other areas supported the hypothesis of differential responsiveness to morphine, both in terms of brain areas affected and response latency. Those brain areas where multiple unit activity responses best fit our operational definition of target sites were the cingulate cortex and hippocampus, and perhaps to a lesser extent, the anterior and medial thalamic nuclei, brain stem reticular formation, cerebral cortex, fimbria/fornix, septum, and substantia nigra. We conclude that multiple unit activity is a sensitive index of opiate effect and that this approach is an appropriate in vivo method to identify and characterize primary sites of opiate action.