Effects of Cannabinoid Agonists on Fentanyl-Induced Respiratory Depression

Abstract ID 128303 Poster Board 315 Prescription opioids remain the most effective treatment for pain despite their addictive and respiratory depressant effects. To overcome this problem, several studies have used non-opioids like cannabinoid CB₁ agonists to enhance opioid analgesia, i.e., opioid-sparing approach. This approach is useful only if the doses of CB₁ agonists that enhance opioid antinociception do not enhance the opioid9s adverse effects. In previous studies, we demonstrated that a partial (AM11101) and full (AM8936) CB₁ agonist enhanced fentanyl's antinociceptive effects in warm water tail withdrawal and formalin assays in a dose-dependent manner. The present studies were conducted to investigate how doses of AM11101 or AM8936 that enhance fentanyl antinociception impact the effects of fentanyl on respiratory function. First, the mouse Ox Plus ® pulse oximeter was used to monitor physiological ventilatory parameters, including arterial oxygen saturation (O₂%) and respiratory rate (RR), in freely moving conscious male CD-1 mice to evaluate the respiratory effects of fentanyl and CB₁ agonists alone. Next, in interaction studies, the effects of CB₁ agonists on fentanyl's respiratory function were determined. Results show that fentanyl (0.032–1.0 mg/kg) alone produced a dose-dependent reduction in O₂% and RR. Interestingly, AM11101 (0.032–0.32 mg/kg) alone did not significantly alter the respiratory function, whereas AM8936 (0.01–0.1 mg/kg) produced a dose-dependent reduction in RR. In interaction studies, pretreatment with doses of AM11101 (0.1–0.32 mg/kg) and AM8936 (0.032–0.1 mg/kg) that enhanced fentanyl antinociception did not significantly alter the respiratory effects of fentanyl. Taken together with our previous studies, the present results suggest that CB₁ agonists can selectively enhance the antinociceptive effects of fentanyl without exacerbating fentanyl's respiratory depressant effects. Future studies will evaluate how doses of CB₁ agonists that enhance fentanyl antinociception impact the abuse-related behavioral and neurochemical effects of fentanyl.