Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects

Abstract

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ⩾30 kg m−2 and binge eating scale scores ⩾19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day−1 GSK1521498, 5 mg day−1 GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day−1 caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day−1 on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Involvement of Endogenous Enkephalins and β-Endorphin in Feeding and Diet-Induced Obesity

“…Such results are interesting when viewed in the context of human genetic screens strongly implicating opioid receptors in obesity phenotypes (Haghighi et al, 2013;Wheeler et al, 2013). Additionally, antagonism of opioid receptors can in some circumstances be effective for reversing such phenotypes in preclinical (Giuliano et al, 2012;Shaw et al, 1991;Statnick et al, 2003) and clinical studies (Cambridge et al, 2013;Ziauddeen et al, 2012). Further understanding of the contributions of opioid transmission to hedonic processing and control of body weight may aid in developing appropriate treatment strategies aimed at pathologies characterized by under-or over-eating.…”

The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking

“…In humans, GSK1521498 also reduced attentional bias to food-related stimuli in obese binge eaters, for whom the food cues had higher motivational value (Ziauddeen et al, 2013a). However, GSK1521498 did not reduce the attentional bias to alcohol-related cues in healthy social drinkers, for whom the motivational properties of alcohol cues may have been low (Ziauddeen et al, 2013b).…”

Changes in mu-opioid receptor expression and function in the mesolimbic system after long-term access to a palatable diet

“…Because activation of mu-opioid receptors promotes consumption of primarily highly palatable food, mu-opioid receptor antagonists or inverse agonists have been of interest in the development of pharmacotherapy for obesity (Ziauddeen et al, 2013;Caixàs et al, 2014). Chronic antagonism of mu-opioid receptors in the NAc can prevent weight gain in rats with access to palatable food (Lenard et al, 2010) and clinical studies using an combination of bupropion, a norepinephrine and dopamine reuptake inhibitor, and naltrexone have demonstrated moderate effects on weight loss in obese individuals (Reece, 2011;Caixàs et al, 2014).…”