NALTRINDOLE RETARDS TOLERANCE DEVELOPMENT TO MORPHINE-INDUCED EFFECTS ON EEG AND EEG POWER SPECTRA

In the present study, EEG and EEG power spectra were used to assess the effects of naltrindole, a selective delta-opioid antagonist, on the development of tolerance to morphine. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling i.c.v. and i.v. cannulas. Twice daily for 7 days, rats were pretreated with either i.c.v. naltrindole (20 nmol) or i.c.v. water, 20 min before i.v. morphine (10 mg/kg) injections. The treatments produced EEG slow-wave bursts and associated behavioral stupor. The amount and duration of these effects decreased less rapidly over the 7 days in the naltrindole-pretreated rats than in the water-pretreated rats. I.c.v. naltrindole pretreatment also prevented significant decreases in latency to onset of slow-wave sleep that were seen in the i.c.v. water-pretreated group. EEG data were further analyzed on a Pathfinder II computer. The development of tolerance was reflected by decreases in the total absolute EEG spectral power (1-50 Hz) over the 7-day period. Rats that were pretreated with i.c.v. naltrindole (20 nmol) did not display a significant decrease in total absolute EEG spectral power by the 7th day, as did the i.c.v. water-pretreated group. Furthermore, significant differences were seen for complexity, mobility, and edge frequency between the two pretreatment groups. A delayed qualitative change in the EEG power spectra was also observed in rats pretreated with i.c.v. naltrindole. On day 1, EEG slow-wave bursts were associated with increases in EEG spectral power over the 1-10 Hz range. However, by day 3, EEG slow-wave bursts were associated with a predominant EEG spectral peak in the 4-6 Hz band. These results further implicate the delta-opioid binding site in the development of tolerance to morphine.