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.
Byford
Alan J
AJ
Department of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire, United Kingdom.
Anderson
Alison
A
Jones
Philip S
PS
Palin
Ronald
R
Houghton
Andrea K
AK
D000818:Animals; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000094942:Nociceptin Receptor
C121726:8-acenaphthen-1-yl-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one; D007093:Imidazoles; D011957:Receptors, Opioid; D013141:Spiro Compounds; D009270:Naloxone; D000094942:Nociceptin Receptor