Vol. 282, Issue 1, 286-293, 1997

EEG Spectral Analysis of the Neuroprotective Kappa Opioids Enadoline and PD117302¹

Frank C. Tortella, Jany Rose, Lydia Robles, J. Edward Moreton, John Hughes and John C. Hunter

Department of Neuropharmacology and Molecular Biology, Walter Reed Army Institute of Research, Washington, DC (F.C.T., L.R., J.R.), Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland (J.E.M.), and Parke-Davis Neurosciences Research Centre, Addenbrookes Hospital Site, Cambridge, CB2 2QB, UK (J.H., J.C.H)

The present study characterized the electroencephalographic (EEG) effects of the neuroprotective kappa opioids enadoline and PD117302 in conscious, freely moving rats with the use of computer-assisted spectral analysis (CASA). Enadoline (25-100 µg/kg) or PD117302 (1.25-5.0 mg/kg) was administered intravenously to rats implanted with cortical EEG electrodes. Although both drugs produced an immediate, mild sedation, there were no signs of head-weaving or ataxia, and there was little visual evidence of opioid-like EEG slow-wave bursts or seizures. Both drugs produced only modest increases in total EEG power that were not dose dependent. In contrast, CASA revealed significant dose-dependent frequency shifts in relative power distributions, thereby identifying distinct kappa opioid alterations in awake EEG activity; EEG power decreased in the 0- to 4-Hz frequency band with concomitant increases in power measured in the 4- to 8-Hz frequency range. The kappa opioids produced a dose-dependent consolidation of the EEG waveform centered about a peak frequency of 5.0 Hz (for enadoline) or 4.8 Hz (for PD117302) and a significant shift in the mean EEG frequency from 6.6 Hz (predrug) to 6.2 Hz (postdrug). Further CASA revealed significant postdrug decreases in the edge frequency, mobility and complexity of the EEG. Both drugs produced moderate increases in the latency to slow-wave sleep (SWS). Overall, enadoline (ED₅₀ = 18 µg/kg) was ~94 times more potent than PD117302 (ED₅₀ = 1690 µg/kg) in producing the kappa EEG profile. Because the kappa-induced EEG changes were stereospecific for the ()-enantiomers and inhibited by norbinaltorphimine (nor-BNI), the EEG "fingerprint" described in this study could be attributed to specific activation of brain kappa opioid receptors.