The benzodiazepine (+)-tifluadom (KC-6128), but not its optical isomer (KC-5911) induces opioid kappa receptor-related EEG power spectra and evoked potential changes.
Tifluadom, a benzodiazepine with purported opioid receptor-related analgesic properties, was studied in regard to its acute effects on power spectra of the EEG to demonstrate vigilance changes. Additionally, somatosensory-evoked potentials (SEP) were derived to evaluate its effect on the propagation of impulses in sensory nerve fibers. In order to demonstrate stereospecificity, the two enantiomers of tifluadom (KC-5911 and KC-6128) were given in graded doses (20, 40, 80, 160 micrograms/kg i.v.) to awake, unrestrained and trained dogs at 10-min intervals. KC-6128, but not its optical counterpart KC-5911, induced synchronization of the EEG at 20 micrograms/kg with an increase of power (pW) in the delta (1-4 Hz; +300%), theta (4-8 Hz; +450%), and alpha (8-13 Hz +90%) bands. This was accompanied by a reduction of power in the fast beta domain (13-30 Hz; -95%). Vigilance changes were reflected in the beta/delta quotient which dropped from 3.7 (control) to 0.8 (20 micrograms/kg) and to 0.3 (40 micrograms/kg). A further increase in the dose resulted in saturation. At the highest dose (160 micrograms/kg) there was an additional reduction of the beta/delta quotient to 0.1. In order to unmask the receptor population, possibly mediating the observed changes, a benzodiazepine antagonist and opioid antagonists were given. Ro 15-1788 (240 micrograms/kg) had no effect and naloxone (20 micrograms/kg) induced a short term (5 min) arousal. Only the kappa antagonist Mr 2266 (20 micrograms/kg) induced a reversal of the beta/delta quotient back to 5.5. KC-5911 induced an insignificant drop in the beta/delta quotient which was reversed by Ro 15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001575:Benzomorphans / Q000494:pharmacology; D004285:Dogs; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism
D001575:Benzomorphans; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D001569:Benzodiazepines; D009270:Naloxone; D005442:Flumazenil; C027247:MR 2266; C035470:tifluadom