The hypnotic, electroencephalographic, and antinociceptive properties of nonpeptide ORL1 receptor agonists after intravenous injection in rodents.

Background: Agonists at the opioid receptor-like receptor 1 (ORL1) induce motor impairment, sedation, and loss of righting reflex (LRR) in rodents. This receptor may provide a novel target in the field of anesthesia.

Methods: We examined the hypnotic, electroencephalographic (EEG), and antinociceptive effects of two IV administered nonpeptide ORL1 agonists, (Ro 65-6570 and Org 26383), using LRR in mice and rats, percent EEG burst suppression in rats, and formalin paw test in mice.

Results: In mice, Ro 65-6570 and Org 26383 produced LRR (hypnotic dose 0.6 and 3.7 micromol/kg for Ro 65-6570 and Org 26383, respectively). Naloxone had no significant effect on sleep times produced by both compounds. In rats, Ro 65-6570 (0.6-2.4 micromol/kg) and Org 26383 (4-8 micromol/kg) produced LRR and burst suppression activity in the EEG. Both sleep times and burst suppression activity were significantly reduced with a selective ORL1 antagonist. In mice, dose-dependent inhibition of formalin-induced nociceptive behaviors occurred (Phase 1 ED50 0.4 and 1.8 micromol/kg and Phase 2 ED50 0.4 and 4.2 micromol/kg for Ro 65-6570 and Org 26383, respectively).

Conclusions: These results show that Ro 65-6570 and Org 26383 (probably via the ORL1 receptor) behave as IV hypnotics and analgesics in mice and rats, and that the hypnotic and antinociceptive doses are similar.