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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.

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.

Introduction: Normative comprehensive echocardiographic measurements data for healthy Indians are not available while data for American and European population is available from American Society of echocardiography and European Society of Cardiology/European Association of Cardio-Vascular Imaging and their publications. Available studies of Indian subjects are small and report only limited measurements with focus on left ventricular (LV) volumes. Objective: We aim to provide comprehensive normative echocardiographic data for healthy Indians from a large sample size. Methods: A retrospective cross-sectional single-center study of 707 healthy Indian adults age and sex segregated which presented detailed and comprehensive echocardiographic measurements including two-dimensional, M-mode, tissue Doppler imaging, speckle tracking echocardiography, chamber volumes, LV ejection fraction (LVEF), global longitudinal strain (GLS), segmental longitudinal strain and effort tolerance. Results: Our findings show healthy Indians, as compared to US and European population, to have higher relative wall thickness. LV volumes, LV mass, LVEF and effort tolerance that were within American Society of Echocardiography described ranges for chamber quantification. Higher GLS values were observed in Indian population compared to European and American population. Women had higher LVEF and GLS values as compared to men and both showed a gradual decline with aging. Conclusion: We present normal reference values for echocardiographic measurements in healthy Indian population, which could be used for future reference and comparison work. Keywords: Echocardiography normative data, Global longitudinal strain, LV ejection fraction, Effort tolerance, Indian adults