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Pain Medicine  |   February 2018
Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling
Author Notes
  • From the Departments of Anesthesiology (C.A., Z.T.G., W.A., S.M., H.A.B., R.L.), Psychology (Z.T.G., H.A.B., R.L.), and Information Technology (J.P.), University of Tennessee, Knoxville, Tennessee; Oak Ridge National Laboratory, Oak Ridge, Tennessee (H.A.B., R.L.); and Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee (Y.J.).
  • This is a Frontiers in Opioid Pharmacotherapy article. Preliminary results have been presented at the American Physiological Society Conference: Cardiovascular, Renal and Metabolic Diseases–Physiology and Gender, Annapolis, Maryland, November 18, 2015, and Experimental Biology, San Diego, California, April 3, 2016.
    This is a Frontiers in Opioid Pharmacotherapy article. Preliminary results have been presented at the American Physiological Society Conference: Cardiovascular, Renal and Metabolic Diseases–Physiology and Gender, Annapolis, Maryland, November 18, 2015, and Experimental Biology, San Diego, California, April 3, 2016.×
  • Submitted for publication July 26, 2017. Accepted for publication November 29, 2017.
    Submitted for publication July 26, 2017. Accepted for publication November 29, 2017.×
  • Research Support: Supported by National Institutes of Health (Bethesda, Maryland) grant No. HL65272, by the Departments of Anesthesiology and Psychology, and by a grant from NeuroNET (University of Tennessee, Knoxville). Also supported by the Beaman Endowed Professorship (to Dr. Baghdoyan) and Robert H. Cole Endowed Professorship (to Dr. Lydic).
    Research Support: Supported by National Institutes of Health (Bethesda, Maryland) grant No. HL65272, by the Departments of Anesthesiology and Psychology, and by a grant from NeuroNET (University of Tennessee, Knoxville). Also supported by the Beaman Endowed Professorship (to Dr. Baghdoyan) and Robert H. Cole Endowed Professorship (to Dr. Lydic).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Lydic: University of Tennessee, Knoxville, Tennessee. rlydic@utk.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Pain Medicine
Pain Medicine   |   February 2018
Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling
Anesthesiology Newly Published on February 1, 2018. doi:10.1097/ALN.0000000000002073
Anesthesiology Newly Published on February 1, 2018. doi:10.1097/ALN.0000000000002073
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.