A high-dose of fentanyl induced delayed anxiety-like behavior in rats. Prevention by a NMDA receptor antagonist and nitrous oxide (N(2)O).

Postoperative negative affects such as anxiety need to be better understood and treated to improve patient recovery. The present study evaluates the effect of a single exposure to a high-dose of opioid (4×100 μg/kg fentanyl injections in 15 min intervals resulting in a total dose of 400 μg/kg), as used for surgery in humans, on anxiety-like behavior (ALB) in rats. First, the level of anxiety was evaluated 24-h after a high-dose of fentanyl using an elevated plus-maze apparatus. Second, the preventive effect of BN2572, a N-methyl-D-aspartate receptor (NMDA-R) antagonist, and 50% nitrous oxide (N(2)O), a gas with NMDA-R antagonist properties, was assessed. A significant increase in ALB was observed in fentanyl-treated rats. Interestingly, fentanyl-induced ALB was prevented by BN2572, suggesting a NMDA-dependant pathway. Fentanyl-induced ALB was also prevented by a single 50% N(2)O exposure. The present study provides evidence that deleterious outcomes of opioid use, referred to as "post-opioid syndrome", include not only pain hypersensitivity as previously described, but also negative affects such as anxiety. Since N(2)O prevents elements of this post-opioid syndrome, we speculate that N(2)O could be a good therapeutic agent to facilitate postoperative rehabilitation.