A Model of Repeated Opioid Use Producing Tolerance to Opioid Induced Respiratory Depression.

Repeated opioid users, such as those who suffer from opioid use disorder, are among the most vulnerable to overdose, overdose-related death, and opioid-related morbidities in breathing in the ongoing epidemic. Despite the significant progress made in defining the cellular and circuit basis by which opioid induced respiratory depression (OIRD) occurs, very little is known about the impact that repeated opioid use (ROU) has on the control of breathing. This ongoing work aims to define how ROU impacts the OIRD. We developed a mouse model of ROU that involved six consecutive days of fentanyl (0.7mg/kg via i.p. injection) administration. Breathing was measured via unrestrained whole-body plethysmography prior to and immediately after fentanyl administration on Day 1 and Day 6. Prior to fentanyl administration, tidal volume (TV), respiratory rate (RR) and minute ventilation (V ) were similar on Day 1 and Day 6 (n= 7 mice). Peak depression of TV during fentanyl was similar on Day 1 and Day 6 (n=7, P=0.28); whereas, peak depression of RR (Day 1: 145.5±19.66 BPM vs. Day 6: 172.0 ± 18.89,P=0.005) and V (Day 1: 142.0±30.23 microL•min •g vs. Day 6: 210.1±21.96 microL•min •g , P=0.04) during fentanyl was greater on Day 1 (n= 6 of 7). Moreover, the change in body temperature during OIRD was not different between Day 1 and Day 6 (Day 1: 0.04±0.021 C vs. Day 6: 0.64 ± 0.021 C, P=0.62). Together these data suggest that tolerance to OIRD emerges following six days of ROU and does not involve significant changes in body temperature. The data from this ongoing study provides foundational knowledge to the impact of ROU on breathing and introduces a novel model of ROU that leads to tolerance to OIRD.