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

Philippe Haouzi, Marissa McCann, Nicole Tubbs

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

We have investigated the potential acute desensitizing role of the b 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 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 b-arr2 pathway-decreased ventilation, but along the V_ E/V_ CO2 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 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, 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 b-arr2-deficient mice. NEW & NOTEWORTHY When life-threatening doses of fentanyl are used in mice, the b-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.

Original languageEnglish (US)
Pages (from-to)1396-1407
Number of pages12
JournalJournal of neurophysiology
Volume125
Issue number4
DOIs
StatePublished - Apr 2021

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Physiology

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