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

Abstract

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 (0.3 mg/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.

Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling

“…First, the ongoing epidemics of opiate abuse 1 and obesity 2 reinforce our interest in opiate research with potential for translational relevance. 3–12 Second, opiate-induced alterations in the ventilatory response to hypercapnia are sexually dimorphic, 13 consistent with evidence that respiratory control is altered by sex steroid hormones. 14 Additional data show that opiate-induced respiratory depression is associated with increased risk among subjects who are female 15 and/or obese.…”

“…This finding is consistent with evidence that body weight alone does not significantly alter the anti-nociceptive effects of buprenorphine. 12…”

“…This possibility is suggested by the fact that leptin, produced by adipocytes, covaries with obesity, and modulates breathing 22–25 and nociception. 7,10,12 Table 1 summarizes similarities and differences between the obesity and leptin phenotypes in the four congenic mouse lines studied. Use of three-way analysis of variance made it possible to evaluate the effects of buprenorphine on breathing as a function of sex, leptin status, and obesity.…”

“…The 0.3 mg/kg dose of buprenorphine has been shown to be antinociceptive in B6 mice 26 and in males and females of the four congenic mouse lines used in this study. 12 Before starting data collection, mice were habituated to being placed in whole body plethysmography chambers (Data Sciences International, St. Paul, MN, USA) where they were free to move and groom. After one week of habituation, mice were randomly assigned to receive either saline or buprenorphine injection and were placed in the plethysmography chambers where breathing was automatically recorded for 1 h. Testing occurred at the same time of day and all mice had one week for recovery between injections.…”

“…Sample sizes (n=80 mice consisting of 10 males and 10 females representing each of the four congenic mouse lines) were based on previous experience. 7,10,12,29 The data were analyzed with Statistical Analysis System v9.4TS1M3 (SAS Institute, Inc., Cary, NC), using a three-way mixed effects, repeated measures analysis of variance (ANOVA) model with two between subject factors (sex and mouse line) and one within subject factor of injection condition (saline vs. buprenorphine). Mouse nested within sex by mouse line was included as a random effect.…”