Peripheral antinociception induced by ketamine is mediated by the endogenous opioid system

Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective mu- and delta-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not kappa-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced beta-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for mu- and delta-opioid receptors and for the endogenous opioid beta-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.