Modulation of opioid overdose susceptibility due to context-dependent tolerance

Abstract

The US is in the midst of an opioid epidemic, which is primarily being driven by repeat opioid use (ROU). The primary cause of opioid overdose is opioid-induced respiratory depression (OIRD). It has been shown that the risk of overdosing, and subsequently death, can change depending on the environment in which the user takes the drug. This phenomenon is called context-dependent tolerance. However, how OIRD changes depending on the location of drug delivery is not known. The objective of this pilot study is to investigate context-dependent respiratory tolerance to OIRD and overdose. We repeatedly paired an injection of fentanyl (0.7 mg/kg/day i.p.) with a distinctive environmental context (fentanyl-paired (FP) environment) and saline with another distinctive context (saline-paired (SP) environment) in adult mice for five days while monitoring breathing via unrestrained whole-body plethysmography. The ROU protocol was followed by two test days where fentanyl was administered in both environments and breathing was measured. We found that minute ventilation was greater during OIRD in the FP environment as compared to the SP environment (n=4). In the second set of mice (n=6?), we tested overdose susceptibility following ROU by administering a high dose of fentanyl (5mg/kg) in both contexts. In contrast to the FP environment where no mice overdosed (n=0/6), n=4/6 mice overdosed in the SP environment. These data suggest a greater susceptibility to OIRD and overdose when in an environment not previously paired with fentanyl administration. This context-dependent effect on OIRD may be a significant psychophysiological factor driving opioid-related deaths in the ongoing opioid epidemic. NIH: R01NS107421; R01HL163965; R01DA057767. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.