OPIOID‐RESISTANT RESPIRATORY RHYTHM SPONTANEOUSLY RESCUING UN‐ANESTHETIZED RATS FOLLOWING FENTANYL OVERDOSE INDUCED APNEA

Abstract

In un‐anesthetized rats, a slow rhythmic respiratory activity spontaneously resumes within tens of seconds following fentanyl overdose induced apnea, rescuing the animals. As this rhythm is produced at a time wherein fentanyl concentrations and receptors occupancy are likely to be extremely high, the mechanisms initiating and sustaining such a respiratory activity remains very unclear.In an attempt to describe the opioid sensitivity and the chemo‐sensitivity of this “rescuing” neo‐rhythm, twenty‐six un‐anesthetized adult rats were studied in an open‐flow plethysmograph. The animals were acutely intoxicated with a bolus intravenous injection of a very high dose fentanyl (300 μg.kg−1), while being exposed to different gas composition (air, 100% O2, 8% CO2/15% O2). All air breathing rats presented an apnea 16 ± 5 seconds into the onset of fentanyl administration and started to generate rhythmic breaths 93 ± 22 seconds into apnea. Ventilation was significantly depressed during this recovery phase along with V̇E/V̇CO2 ratio. Neither hyperoxia nor hypercapnia affected the time at which a spontaneous respiratory rhythm was produced or the level of ventilation that ensued. At 10 minutes, the animals were randomly divided into 2 groups: one group immediately received a second injection of fentanyl, while the other group received a second dose at 30 minutes. No apneas were produced after a second injection of fentanyl in 100% and 70% of the rats at 10 and 30 minutes respectively.The rhythmic breathing activity that rescues fentanyl overdose‐induced apnea is chemo‐insensitive and opioid resistant for at least 30 minutes. Investigating the mechanisms of desensitization involved in this survival mechanism, which develops within tens of seconds – and whether or not such a mechanism relies on the opioid phosphorylation of G coupled receptors/beta arrestin 2 interactions – could lead to a better understanding of the mechanisms leading to a fatal outcome of fentanyl induced apnea and possibly to the development of new countermeasures against opioid overdose.Support or Funding InformationNONEExample of the effects of injections of fentanyl (300 microg.kg−1.min−1 over one minute) on instantaneous respiratory flow and minute ventilation 10 minutes apart in an unseated rat (open‐flow body plethysmography). A long central apnea occurred almost immediately after the first injection (first bout) followed by the emergence of a spontaneous rhythmic breathing with slow frequency and low tidal volume. A subsequent injection, 10 minutes later, produced almost no change in breathing.Figure 1