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

Abstract

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.

Biased Agonism: Lessons from Studies of Opioid Receptor Agonists

“…In stark contrast to the original report (26), each laboratory found that the ability of morphine to depress respiration was the same with or without the presence of β-arrestin 2. Since then, this finding has been confirmed in no fewer than four further studies (29)(30)(31)(32). Indeed, one of those studies (30) found that following high doses of fentanyl, mice lacking β-arrestin 2 were actually more likely to stop breathing and die than were wild-type mice, a result that certainly does not indicate that G protein-biased agonists at the μ-opioid receptor will be safer.…”

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

“…Favourable oliceridine safety profile over morphine when considering emesis 96 and respiratory depression 97 was also reported in human. But other studies applying genetic 98 , 99 , pharmacological 72 or mixed 100 , 101 approaches reported severe adverse effects associated with G-protein biased MOR agonists. Thus, it is unclear if no/reduced efficacy for β -arrestin-2 recruitment by WLB-73502 accounts for its improved side effect profile.…”

Effect of Positive Allosteric Modulation and Orthosteric Agonism of Dopamine D2 Receptors on Respiration in Mouse Models of Rett Syndrome

“…The effect on locomotor activity could also account for some of the reduction in irregularity of breathing, however, it is unlikely to account for the dramatic reduction in apnea frequency, which is a hallmark of the breathing disturbances in RTT mice even in reduced preparations (Abdala et al, 2010(Abdala et al, , 2014. The quinpirole-induced reduction in body temperature and locomotor activity also suggests reductions in metabolic rate, which can stabilize breathing (Gautier, 1996;Haouzi et al, 2021). Thus, the stabilization of breathing observed after quinpirole treatment could be secondary to metabolic and locomotor activity changes.…”