Buprenorphine‐Induced Respiratory Depression Varies as a Function of Leptin‐Related Genotype in Normal Weight and Obese Mice
Authors: Angel Chelsea , Alami Wateen , Mihalko Sara , Baghdoyan Helen A , Lydic Ralph 
Published: November 2023

Most obesity is polygenic with comorbidities that include increased reports of pain (J Pain Res 8: 399, 2015) and opiate‐induced respiratory depression (Anesthesiology 122: 659, 2015). Adipocytes produce leptin and obese, leptin‐deficient mice exhibit state‐dependent respiratory depression (Resp Physiol 119: 173, 2000) as well as altered nociception (Neuroscience 275: 531, 2014). Here we report pre‐clinical studies testing the hypothesis that buprenorphine‐induced respiratory depression is greater in mice lacking leptin or leptin receptors than in normal mice. These studies have quantified buprenorphine‐induced changes in breathing in C57BL/6J (B6) mice that have normal levels of leptin; B6.BKS(D)‐Leprdb/J (db/db) mice that lack leptin receptors, are obese, and diabetic; and B6.Cg‐Lepob/J (ob/ob) mice that lack leptin and are obese. Mice (10 males and 10 females of each genotype) were purchased from The Jackson Laboratory and studied in accordance with the FASEB Statement of Principles for animal research. Mice received intraperitoneal injections (0.3 mL) of saline (control) or buprenorphine at concentrations of 0.1, 0.3, 1.0, 3.0, or 10 mg/kg. After each injection, breathing was measured for one hour using whole body plethysmography (DSI, St. Paul, MN, USA). At all doses, minute ventilation (mL/min/g body weight) of B6 mice was about three‐fold greater than in obese db/db and ob/ob mice. Two‐way ANOVA revealed that minute ventilation varied significantly by dose for male (F=3.47; df=5,135; p=0.0056) and female (F=4.18; df=5,135; p=0.0015) mice, by genotype for males (F=159; df=2,27; p<0.0001) and females (F=332; df=2,27; p<0.0001), and the dose by genotype interaction was statistically significant for both male and female mice. Respiratory duty cycle (duration of inspiration/total respiratory cycle time), the proportion of the respiratory cycle spent in the active inspiratory phase, at all doses was lower in B6 than in ob/ob and db/db mice. Duty cycle also varied by dose in males (F=6.93; df‐5,135; p<0.001) and females (F=23.75; df=5,135; p<0.0001), by genotype in males (F=48; df=2,27; p<0.0001) and females (F=19.76; df=2,27; p<0.0001), and the interaction term was statistically significant. Inspiratory flow (tidal volume/duration of inspiration) in mL/s, an index of ventilatory drive, was lower at every buprenorphine dose in both sexes of ob/ob and db/db mice than in the B6 mice. Inspiratory flow varied by dose for males (F=19.72;df‐5,135; p<0.0001) and females (F=29.9;df=5,135;p<0.0001), by genotype for males (F=29.97;df=2,27; p<0.0001) and females (F=8.79;df=2,27; p=0.001), and the dose by genotype interaction was statistically significant. Taken together, these data support the interpretation that the desirable ceiling effect of buprenorphine for respiratory depression is diminished in obese mice with dysfunctional leptin. Ongoing studies include mice with phenotypes of diet‐induced obesity and normal leptin.

Support or Funding Information

NIH Grant HL065272 and Departments of Anesthesiology and Psychology