Opioid‐induced suppression of augmented breaths (‘sighs’) persists during extended morphine administration at sub‐analgesic dosage

Abstract

Our previous work has demonstrated that acute morphine administration causes powerful suppression of augmented breaths (ABs) at the low‐to‐mid dosage range for analgesia in adult rats. The present study was performed to determine the extent to which this suppression of ABs persists in the course of prolonged morphine administration. We studied breathing non‐invasively in adult rats in 2 separate experiments: Exp 1: animals were monitored immediately before, and repeatedly following s.c. bolus injections of morphine, 4 mg/kg loading dose and maintenance doses of 2 mg/kg given each hour for 8 consecutive hours (n=8). Exp 2: Animals were monitored immediately before and again repeatedly across 10 consecutive days of morphine treatment self‐administered via oral dosing in drinking water (n=7). Appropriate sham/control experiments were performed using saline injections and normal drinking water. In Exp 1, morphine injection caused a potent suppression of ABs, observed immediately upon first injection (6.0 ± 2.9 vs 0.5 ± 0.5 ABs/15 min, pre vs. post), and persisting throughout the 8 hours of study (P<0.001). This occurred despite there being no depression of minute ventilation. The prevalence of ABs in the sham injection condition remained unchanged across the 8 hours of study. In Exp 2, morphine concentration in drinking water was titrated up to 0.4 mg/mL across days 1 to 5, and remained constant at 0.4 mg/mL through day 10. This concentration was chosen so as to avoid taste aversion and drinking abstinence commonly seen when attempting to use higher concentrations of morphine. Animals self‐administered an average of 33.1 ± 6.9 mg/day (1.4 mg/kg/hr) on day 7 and 36.6 ± 3.4 mg/kg/day (1.5 mg/kg/hr) on day 10. This relatively low dosage was sub‐analgesic in efficacy as confirmed by lack of prolongation of tail flick latency. Despite the low dosage, continuously administered morphine caused significantly fewer ABs to be expressed on day 10 of morphine treatment (3.3 ± 1.5 ABs/15 min) compared to either pre‐treatment (7.0 ± 1.8) or day 10 of the control (6.3 ± 1.8) condition. No depression of minute ventilation was observed across the 10 days of treatment. These results confirm that the opioid‐induced suppression of ABs occurs rapidly and persists across extended treatment of at least 10 days. Moreover, this side effect occurs even in the sub‐analgesic dose range in the absence of any depression of minute ventilation.Support or Funding InformationThis work was supported by research funds provided by the Central Michigan University College of Medicine, and an Early Career Grant awarded by the Office of Research and Sponsored Programs at Central Michigan University.