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Anesth Analg 2007;104:174-179
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000250403.88649.51

ANALGESIA

The Hypnotic, Electroencephalographic, and Antinociceptive Properties of Nonpeptide ORL1 Receptor Agonists After Intravenous Injection in Rodents

Alan J. Byford, MSc*, Alison Anderson*, Philip S. Jones, PhD{dagger}, Ronald Palin, PhD{dagger}, and Andrea K. Houghton, PhD*

From the Departments of *Pharmacology and {dagger}Chemistry, Organon Laboratories Ltd, Newhouse, Lanarkshire, ML1 5SH, United Kingdom.

Address correspondence and reprint requests to Andrea K. Houghton, PhD, Department of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire, ML1 5SH, United Kingdom. Address e-mail to a.houghton{at}organon.co.uk.

Abstract

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 µmol/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 µmol/kg) and Org 26383 (4–8 µmol/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 µmol/kg and Phase 2 ED50 0.4 and 4.2 µmol/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.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2007 by the International Anesthesia Research Society.