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 β arrestin 2 (β-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 β-arr2-deficient nonsedated 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 β-arr2 pathway-decreased ventilation, but along the V̇e/V̇co2 relationship established in baseline conditions. This reduction in ventilation was therefore indistinguishable from the decrease in breathing during the periods of spontaneous immobility. Above 1.5 mg/kg, however, ventilation was depressed out of proportion of the changes in metabolic rate, suggesting a specific depression of the drive to breathe. The ventilatory responses were similar between the two groups. At high doses of fentanyl (60 mg/kg ip) 1 out of 20 control mice died by apnea versus 8 out of 20 β-arr2-deficient mice (P = 0.008). In the surviving mice, ventilation was however identical in both groups. The ventilatory effects of fentanyl in β-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 β-arr2-deficient mice, mechanisms of which are still open to question, as the capacity of maintaining a rhythmic, although profoundly depressed, breathing activity remains similar in all of the surviving control and β-arr2-deficient mice.NEW & NOTEWORTHY When life-threatening doses of fentanyl are used in mice, the β-arrestin 2 pathway appears to play a critical role in the recovery from opioid overdose. This observation calls into question the use of G protein-biased μ-opioid receptor agonists, as a strategy for safer opioid analgesic drugs.

• Authors: Philippe Haouzi, Marissa McCann, Nicole Tubbs
• Journal: Journal of neurophysiology (J Neurophysiol) Vol. 125 Issue 4 Pg. 1396-1407 (04 01 2021) ISSN: 1522-1598 [Electronic] United States
• PMID: 33656934 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics, Opioid
• Arrb2 protein, mouse
• beta-Arrestin 2
• Fentanyl

Topics

• Analgesics, Opioid (administration & dosage, adverse effects, pharmacology)
• Animals
• Apnea (chemically induced)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Female
• Fentanyl (administration & dosage, adverse effects, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Opiate Overdose (metabolism)
• Respiration (drug effects)
• Signal Transduction (drug effects)
• beta-Arrestin 2 (deficiency, metabolism)