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Antinociception by intrathecal delivery of the novel non‐opioid 1‐amino‐1‐cyclobutanecarboxylic acid
Author(s) -
Fung Timothy,
Asiri Yahya I.,
Taheri Kamyar,
Wall Richard,
Schwarz Stephan K. W.,
Puil Ernest,
MacLeod Bernard A.
Publication year - 2019
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1301
Subject(s) - medicine , pharmacology , opioid , anesthesia , nociception , saline , epidural administration , morphine , systemic administration , amino acid , nmda receptor , intrathecal , antagonist , receptor , chemistry , in vivo , biochemistry , biology , microbiology and biotechnology
Background Neuraxial opioids are widely used for intraoperative and post‐operative 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 to determine whether 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 anaesthetized 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 min. 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 GABA B 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. Significance The novel, non‐opioid analgesic, 1‐amino‐1‐cyclobutanecarboxylic acid, produced robust, reversible and localized antinociception in murine models of pain. This study provides evidence supporting further investigation and development of 1‐amino‐1‐cyclobutanecarboxylic acid as a non‐opioid spinal analgesic.