Antinociceptive properties of neurosteroids I. Spinally-mediated antinociceptive effects of water-soluble aminosteroids

Four water-soluble aminosteroid intravenous anaesthetic agents (ORG 20380, 20549, 21047 and 20599) were investigated for antinociceptive properties following intrathecal injection in rats, Two compounds, ORG 20380 and 20549, produced spinally-mediated antinociception assessed by tail flick and electrical current nociceptive tests. These effects were dose-related and suppressed by concurrent administration of the GABAA receptor antagonist, bicuculline. ORG 21047 and 20599 caused no antinociceptive effects when given intrathecally. Experiments in which nociceptive thresholds were measured after intravenous injections of ORG 20549 showed that sub-anaesthetic doses of this compound caused antinociceptive effects revealed by both nociceptive tests. This was equal in magnitude to that obtained with intrathecal administration of the same drug. We conclude that ORG 20380 and 20549 produce spinally-mediated antinociception by combination with spinal cord GABAA receptors. These spinal receptors are different from the GABAA receptors responsible for the anaesthetic effects of these drugs. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.