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Antinociception by Intrathecal Delivery of the Novel Non-Opioid 1-Amino-1-Cyclobutanecarboxylic Acid.
European Journal of Pain : EJP 2018 August 10
BACKGROUND: Neuraxial opioids are widely used for intraoperative and postoperative analgesia. The risk of severe adverse effects including respiratory depression accompanies this analgesia, prompting the need for effective non-opioid alternatives. Systemic 1-amino-1-cyclobutanecarboxylic acid showed promise in preliminary studies to produce antinociception without observable toxicity. However, the effects of 1-amino-1-cyclobutanecarboxylic acid after intrathecal administration are unknown. The aim of this study was determine if intrathecal administration of 1-amino-1-cyclobutanecarboxylic acid produces antinociceptive effects in murine models and to elucidate its site and receptor mechanism of action.
METHODS: Female CD-1 mice were randomized to receive intrathecal, intraperitoneal and intraplantar injections of 1-amino-1-cyclobutanecarboxylic acid. Animals receiving intrathecal injections were anesthetized and injected between L5 and L6. Animals then received an intraplantar injection of 10% hypertonic saline into the right hindpaw and were video recorded for 30 minutes. Videos were analyzed by a blinded observer who determined the duration that animals exhibited nocifensive responses.
RESULTS: Intrathecal or intraperitoneal administration of 1-amino-1-cyclobutanecarboxylic acid reduced the time that animals exhibited nocifensive behaviour whereas intraplantar administration produced no effect. The effects of intrathecal 1-amino-1-cyclobutanecarboxylic acid were restricted in dermatomal distribution, reversible and produced little or no depression of respiratory rate. An NMDA antagonist blocked antinociception while mu-opioid or GABAB antagonists did not prevent ACBC antinociception.
CONCLUSIONS: Intrathecal 1-amino-1-cyclobutanecarboxylic acid in mice produces robust, brief antinociceptive effects with a dermatomal distribution corresponding to the lumbar site of administration. This amino acid merits further exploration as a non-opioid neuraxial analgesic with little or no respiratory side effects. This article is protected by copyright. All rights reserved.
METHODS: Female CD-1 mice were randomized to receive intrathecal, intraperitoneal and intraplantar injections of 1-amino-1-cyclobutanecarboxylic acid. Animals receiving intrathecal injections were anesthetized and injected between L5 and L6. Animals then received an intraplantar injection of 10% hypertonic saline into the right hindpaw and were video recorded for 30 minutes. Videos were analyzed by a blinded observer who determined the duration that animals exhibited nocifensive responses.
RESULTS: Intrathecal or intraperitoneal administration of 1-amino-1-cyclobutanecarboxylic acid reduced the time that animals exhibited nocifensive behaviour whereas intraplantar administration produced no effect. The effects of intrathecal 1-amino-1-cyclobutanecarboxylic acid were restricted in dermatomal distribution, reversible and produced little or no depression of respiratory rate. An NMDA antagonist blocked antinociception while mu-opioid or GABAB antagonists did not prevent ACBC antinociception.
CONCLUSIONS: Intrathecal 1-amino-1-cyclobutanecarboxylic acid in mice produces robust, brief antinociceptive effects with a dermatomal distribution corresponding to the lumbar site of administration. This amino acid merits further exploration as a non-opioid neuraxial analgesic with little or no respiratory side effects. This article is protected by copyright. All rights reserved.
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