Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice.

BACKGROUND The involvement of the mu-opioid receptor (muOR) system in the control of breathing, anesthetic potency, and morphine- and anesthesia-induced respiratory depression was investigated in mice lacking the muOR. METHODS Experiments were performed in mice lacking exon 2 of the muOR gene (muOR-/-) and their wild-type littermates (muOR+/+). The influence of saline, morphine, naloxone, and sevoflurane on respiration was measured using a whole body plethysmographic method during air breathing and elevations in inspired carbon dioxide concentration. The influence of morphine and naloxone on anesthetic potency of sevoflurane was determined by tail clamp test. RESULTS Relative to wild-type mice, muOR-deficient mice displayed approximately 15% higher resting breathing frequencies resulting in greater resting ventilation levels. The slope of the ventilation-carbon dioxide response did not differ between genotypes. In muOR+/+ but not muOR-/- mice, a reduction in resting ventilation and slope, relative to placebo, was observed after 100 mg/kg morphine. Naloxone increased resting ventilation and slope in both genotypes. Sevoflurane at 1% inspired concentration induced similar reductions in resting ventilation and slope in the two genotypes. Anesthetic potency was 20% lower in mutant relevant to wild-type mice. Naloxone and morphine caused an increase and decrease, respectively, in anesthetic potency in muOR+/+ mice only. CONCLUSIONS The data indicate the importance of the endogenous opioid system in the physiology of the control of breathing with only a minor role for the muOR. The muOR gene is the molecular site of action of the respiratory effects of morphine. Anesthetic potency is modulated by the endogenous mu-opioid system but not by the kappa- and delta-opioid systems.