Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling.

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.

Leptin status alters buprenorphine-induced antinociception in obese mice with dysfunctional leptin receptors.

Buprenorphine is an opiate used for pain management and to treat opiate addiction. The cytokine leptin can modulate nociception, but the extent to which buprenorphine-induced antinociception varies as a function of leptin signaling has not been characterized. Four congenic mouse lines with phenotypes that include differences in body weight and leptin status were used to test the hypothesis that the antinociceptive effects of buprenorphine vary as function of sex and leptin signaling. Each mouse line was comprised of males (n=12) and females (n=12) for a total of 96 animals. Groups included C57BL/6J (B6) mice (wild type), B6 mice with diet-induced obesity (DIO), obese B6.Cg-Lepob/J (ob/ob) mice lacking leptin, and obese B6.BKS(D)-Leprdb/J (db/db) mice with dysfunctional leptin receptors. The dependent measure was tail flick latency (TFL) in seconds for mouse-initiated tail removal from a warm water bath. Independent variables were intraperitoneal administration of saline (control) or buprenorphine (0.3mg/kg). Within every mouse line, buprenorphine significantly increased TFL relative to saline. Compared to the other mouse lines, db/db mice with dysfunctional leptin receptors had a significantly longer TFL after saline and after buprenorphine. TFL did not vary significantly by body weight or sex. The results provide novel support for the interpretation that acute thermal nociception is associated with altered leptin signaling.