Respiratory effects of low and high doses of fentanyl in control and β-arrestin 2 deficient mice.

We have investigated the potential acute desensitizing role of the beta arrestin 2 (b-arr2) pathway on the ventilatory depression produced by levels of fentanyl ranging from analgesic to life-threatening (0.1 to 60 mg/kg IP) in control and b-arr2 deficient non-sedated mice. Fentanyl at doses of 0.1, 0.5 and 1 mg/kg IP - corresponding to the doses previously used to study the role of b-arr2 arrestin pathway - decreased ventilation, but along the V̇E/V̇CO2 relationship established in baseline conditions, which was therefore indistinguishable from animals that were immobile. Above 1.5 mg/kg, however, ventilation was depressed out of proportion of the changes in metabolism, suggesting a specific depression of the drive to breathe. The ventilatory responses were similar between the 2 groups. At high doses of fentanyl (60 mg/kg IP) one out of 20 control mice died by apnea versus 8 out of 20 b-arr2 deficient mice (P=0.008). In the surviving mice, ventilation was however identical in both groups. The ventilatory effects of fentanyl in b-arr2 deficient mice reported in the literature are primarily mediated by the "indirect" effects of sedation/hypometabolism on breathing control. There was an excess mortality at very high doses of fentanyl in the b-arr2 deficient mice, which mechanisms are still open to question, since the capacity of maintaining a rhythmic, although profoundly depressed, breathing activity remains similar in all of the surviving control and b-arr2 deficient mice.