Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling

• Published in: Anesthesiology (Philadelphia) 2018-05, Vol.128 (5), p.984-991
• Main Authors: Angel, Chelsea, Glovak, Zachary T, Alami, Wateen, Mihalko, Sara, Price, Josh, Jiang, Yandong, Baghdoyan, Helen A, Lydic, Ralph
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - adverse effects; Animals; Buprenorphine - adverse effects; Disease Models, Animal; Female; Leptin - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity - physiopathology; Respiratory Insufficiency - chemically induced; Sex Factors; Signal Transduction - physiology
• ISSN: 0003-3022; 1528-1175; 1528-1175
• DOI: 10.1097/ALN.0000000000002073

BACKGROUND:Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing. METHODS:Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincaré analyses. RESULTS:Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincaré analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation. CONCLUSIONS:The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincaré plots illustrate that the buprenorphine-induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress.