μ-opioid receptor system mediates reward processing in humans

The endogenous μ-opioid receptor (MOR) system regulates motivational and hedonic processing. We tested directly whether individual differences in MOR are associated with neural reward responses to food pictures in humans. We scanned 33 non-obese individuals with positron emission tomography (PET) using the MOR-specific radioligand [11C]carfentanil. During a functional magnetic resonance imaging (fMRI) scan, the subjects viewed pictures of appetizing versus bland foods to elicit reward responses. MOR availability was measured in key components of the reward and emotion circuits and used to predict BOLD-fMRI responses to foods. Viewing palatable versus bland foods activates regions involved in homeostatic and reward processing, such as amygdala, ventral striatum and hypothalamus. MOR availability in the reward and emotion circuit is negatively associated with the fMRI reward responses. Variation in MOR availability may explain why some people feel an urge to eat when encountering food cues, increasing risk for weight gain and obesity. Opioids and reward 3 Introduction The human reward system promotes motivated behaviour toward signals providing safety and opportunities for homeostasis. The endogenous opioid system is intimately involved in both hedonic functions and incentive motivation, and also in generating pleasurable sensations when consuming palatable foods . Injection of μ-opioids into the mesolimbic reward system is rewarding in its own right , and μ-opioids receptor (MOR) stimulation in the shell of nucleus accumbens increases pleasure obtained from foods and may also promote feeding . Similarly, opioid agonists increase and opioid antagonist decrease food intake and hedonic responses to palatable foods, respectively 5-8 whereas inverse MOR agonists diminish hedonic impact of feeding . These data are paralleled by human imaging work showing that feeding triggers endogenous opioid release , possibly contributing to pathophysiology of obesity. Repeated overstimulation of the MOR system following food consumption may lead to lasting downregulation of MOR, thus providing a candidate neurobiological mechanism that reinforces overeating in obese individuals. Indeed, positron emission tomography (PET) studies have established that MOR levels are downregulated in patients with morbid obesity and binge-eating disorder . In addition to homeostatic signaling, feeding involves preferences and habits that have been established by repeated reinforcing rewards. Numerous functional magnetic resonance imaging (fMRI) studies have established that merely viewing food-related cues engage the brain’s reward circuit , possibly promoting food-seeking behavior. Indeed both obese subjects 18-20 and individuals with high genetic risk for obesity 21 show increased reward circuit responses when seeing pictures of foods. Individual differences in reward drive are associated with both cerebral MOR availability 22 and reward circuit responses to food cues . Because MOR downregulation is a hallmark of overeating and obesity , individual differences in MOR system could mediate reward responses and concomitant urges to eat when encountering food cues such as pictures in advertisements. However, this hypothesis currently lacks direct empirical support. Figure 1. Experimental design for fMRI. Subjects viewed alternating 15.75-s epochs with appetizing foods, bland foods or cars. Each block contained six stimuli from one category, intermixed with fixation crosses. Opioids and reward 4 Here we show that individual differences in limbic and frontocortical MOR availability are associated with reward circuits’ responses to visual food cues in healthy non-obese individuals. We measured brain MOR availability using PET with [C]carfentanil, a specific radioligand for MOR, and extracted the availability of MOR in key components of the reward and emotion circuit, as well as globally in in the brain. We then had participants undergo an fMRI scan where they viewed pictures of appetizing and bland foods (Fig 1), while their attention was focused away from the hedonic and motivational aspects of the pictures. Based on prior observations on hypoactive reward responses to food cues in the obese , endogenous opioid release following feeding , and lower MOR density as a compensatory desensitization phenomenon due to overstimulation of MOR by endogenous opioids 10,12,13 we expected to see largest BOLD-fMRI reward responses in subjects with lowest MOR availability. We show that such implicit reward processing activates frontal, striatal and limbic components of the reward circuit, and that the magnitude of the anticipatory reward responses is linearly associated with the MOR availability in the reward circuit. Such variation MOR-dependent reward responsiveness may explain why some people feel an urge to eat when encountering food cues, increasing risk for weight gain and obesity. Figure 2. Mean distribution of MOR in the brain as measured with [C]carfentanil (n = 33) showing widespread MOR expression with highest densities in striatum, thalamus, and