Investigating the role of the Locus Coeruleus in context-dependent respiratory tolerance to opioids

Pairing an environmental context with repeat opioid use (ROU) can result in increased tolerance to the effects of the opioid. This context-dependent tolerance has been extensively studied with respect to the analgesic effects of opioids, yet a knowledge gap exists in understanding whether there is context-dependent tolerance that develops in opioid induced respiratory depression (OIRD). While activity in the Locus Coeruleus (LC), the primary noradrenergic center of the brain, is involved in cue-reward related behaviors, it also enhances breathing in response to changes in blood gas homeostasis. The objective of this study is to investigate the role of the LC in context-dependent respiratory tolerance. Adult mice expressing GCaMP in the noradrenergic cells of the LC underwent a ROU protocol consisting of an initial five-day period of context pairing where each mouse was administered fentanyl (0.7mg·kg-1·day-1; i.p.) in a distinctive fentanyl-paired context (FP), and saline was administered in different distinctive saline-paired (SP) context. Following context pairing, each mouse was administered fentanyl in both the FP and SP, while LC activity and breathing were simultaneously assessed using fiber photometry and unrestrained whole body plethysmography, respectively. Independent of context, fentanyl administration caused LC activity to increase and become rhythmic during OIRD (n=6). In the FP, however, the OIRD nadir occurred 10 min after fentanyl in all subjects (n=6/6); whereas the OIRD nadir in the SP occurred 5 min after fentanyl administration in the majority of subjects (n=5/6). The difference in time to OIRD nadir corresponded to a greater amount of LC activity in the FP prior to fentanyl (n=5 of 6, p=0.03) and during OIRD (n=5 of 6, p=0.021). These results implicate the potential involvement of LC activity and increased central noradrenergic status in producing context-dependent tolerance delaying the OIRD nadir. Our findings may be leveraged to better predict and/or mitigate overdose-related deaths associated with ROU. 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.