What question did this study set out to answer?

This research aims to understand how different doses of morphine affect the synchronization of breathing with locus coeruleus activity.

May 14, 2026

Low-Dose Morphine Attenuates Respiratory-Synchronized Locus Coeruleus Activity Under Normoxic and Hypercapnic Conditions

Key Points

This research aims to understand how different doses of morphine affect the synchronization of breathing with locus coeruleus activity.
Investigated respiratory-LC synchronization using fiber photometry and plethysmography in Dbh-Cre + mice.
Administered morphine at doses of 10, 30, and 100 mg/kg under normoxic and hypercapnic conditions.
Analyzed event-triggered averages to assess changes in LC calcium transients pre- and post-morphine administration.
10 mg/kg morphine significantly reduced peak GCaMP7f activity by 56.6% in normoxia and 45.9% in hypercapnia (p < 0.01).
Higher doses (30 mg/kg and 100 mg/kg) did not show significant disruptions (all p > 0.1).
Event-triggered response waveforms maintained similar morphology across conditions, despite amplitude decreases.

Abstract

Opioid-induced respiratory depression (OIRD) is a leading cause of overdose mortality. Although opioids like morphine reduce respiratory drive through multiple mechanisms within key respiratory centers, their direct effects on neuromodulatory brain regions and how these influence breathing remain poorly understood. A deeper, mechanistic understanding of these processes could provide tools to prevent fatalities associated with OIRD. The locus coeruleus (LC) is the brain’s main source of noradrenaline and modulates breathing via arousal and CO 2 sensitivity and is characterized by a dense population of opioid receptors, especially µ-opioid receptors. In this study, we investigated the interplay between breathing and LC activity and assessed how different doses of morphine influence it. We hypothesized that respiration is synchronized to LC activity and that morphine would dose-dependently diminish this coordination with higher doses producing stronger disruption. After selective expression of Cre-dependent GCaMP7f virus in the LC of Dbh-Cre + mice, simultaneous recordings of LC calcium transients (fiber photometry) and respiration (plethysmography) were performed in freely behaving adults. These real-time calcium transients were time-locked to the onset of spontaneous respiratory rate acceleration events under normoxic (room air) and hypercapnic (7% CO 2 ) conditions, both before and after systemic administration of morphine at three different doses (10, 30, or 100 mg/kg, i.p.). Analysis of normalized event-triggered averages (paired t-tests) revealed that spontaneous respiratory accelerating events reliably evoke strong LC transients under baseline conditions, demonstrating robust respiratory-LC synchronization. Administration of the lowest morphine dose (10 mg/kg, n = 9) significantly desynchronized LC transients, reducing the peak GCaMP7f activity by 56.6% in normoxia and 45.9% in hypercapnia (both p 0.1). The GCaMP7f waveform morphology of event triggered responses was preserved across conditions, suggesting that the temporal dynamics of respiratory-LC synchronization remain intact even when amplitude is significantly attenuated. Our results show that low-dose morphine maximally disrupts respiratory-LC synchronization while substantially higher doses preserve this physiological relationship. These intriguing results have important implications for understanding individual variability in susceptibility to OIRD and could inform strategies for risk assessment in patients receiving opioid therapy. Thomas H. Maren Research Excellence Award to A. G. V. NIH/NHLBI K99/R00 HL159232 to A. G. V. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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