Buprenorphine depresses respiratory variability in obese mice with altered leptin signaling

Chelsea Angel, Zachary T. Glovak, Wateen Alami, Sara Mihalko, Josh Price, Yandong Jiang, Helen Baghdoyan, Ralph Lydic

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)984-991
Number of pages8
JournalAnesthesiology
Volume128
Issue number5
DOIs
StatePublished - Jan 1 2018

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Obese Mice
Buprenorphine
Leptin
Ventilation
Obesity
Body Weight
Opiate Alkaloids
Whole Body Plethysmography
Leptin Receptors
Respiratory Insufficiency
Analysis of Variance
Respiration
Regression Analysis
Diet

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

Buprenorphine depresses respiratory variability in obese mice with altered leptin signaling. / Angel, Chelsea; Glovak, Zachary T.; Alami, Wateen; Mihalko, Sara; Price, Josh; Jiang, Yandong; Baghdoyan, Helen; Lydic, Ralph.

In: Anesthesiology, Vol. 128, No. 5, 01.01.2018, p. 984-991.

Research output: Contribution to journalArticle

Angel, Chelsea ; Glovak, Zachary T. ; Alami, Wateen ; Mihalko, Sara ; Price, Josh ; Jiang, Yandong ; Baghdoyan, Helen ; Lydic, Ralph. / Buprenorphine depresses respiratory variability in obese mice with altered leptin signaling. In: Anesthesiology. 2018 ; Vol. 128, No. 5. pp. 984-991.
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abstract = "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 Poincar{\'e} 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). Poincar{\'e} 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. Poincar{\'e} 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.",
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