Review
Cannabinoids, opioids and eating behavior: The molecular face of hedonism?

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Abstract

Obesity represents nowadays one of the most devastating health threats. Published reports even project a decline in life expectancy of US citizens due to the rapidly increasing prevalence of obesity. This alarming increase is intimately linked with recent changes of environment and lifestyle in western countries. In this context, the rewarding or even addictive properties of popular food may represent one of the most serious obstacles to overcome for an effective anti-obesity therapy. Therefore, in addition to molecular networks controlling energy homeostasis, now researchers are starting to define central nervous mechanisms governing hedonic and addictive components of food intake.

A recently emerging body of data suggests that the endogenous cannabinoid and opioid systems both represent key circuits responding to the rewarding value of food. This review focuses on the role of these two systems for the homeostatic and hedonic aspects of eating behavior and includes their anatomical and functional interactions. Independent from the degree to which eating can be considered an addiction, cannabinoid and opioid receptor antagonists are promising anti-obesity drugs, since they are targeting both hedonic and homeostatic components of energy balance control.

Introduction

Obesity is defined as a disease that results from the imbalance between energy intake and energy expenditure needs. Since obesity and its consequences, such as type 2 diabetes, cardiovascular diseases and cancer, are a serious health threat, it is mandatory that an effective and safe pharmacological treatment becomes available soon (Gura, 2003). The worldwide shocking increase of the obesity prevalence is strongly related to changes in environment and lifestyle (Hill et al., 2003). Decreased physical activity and overconsumption of food synergistically promote body weight increase, and the rewarding properties of popular food in western societies represent yet another obstacle for effective anti-obesity drugs (Hill et al., 2003). Thus, in many obese individuals, the homeostatic mechanisms regulating energy balance that otherwise would work perfectly are overpowered by environmental influences.

Reward and motivation have been extensively studied in the context of drug addiction, and recent evidence has suggested that addiction to food and to drugs may be based on overlapping neuronal pathways. In fact, both feeding and drug use are characterized by learned habits and preferences that are acquired and stamped by powerful rewarding reinforces (Volkow and Wise, 2005). The corticolimbic circuits which are thought to be responsible for pleasure as a natural reward associated with food or sex are implicated as well in addiction and addiction-related phenomena, such as tolerance, withdrawal and relapse (Saper et al., 2002). During the last years, a substantial body of data indicates that the endogenous cannabinoid and opioid systems play a key role both in feeding and in reward (Cota et al., 2003a, Tanda and Goldberg, 2003) and might functionally interact with each other (Manzanares et al., 1999, Tanda and Goldberg, 2003). This overview attempts to present a complete analysis of the multiple interactions between these two systems with particular focus on their importance for the regulation of food intake and on their role as potential valuable target for the treatment of obesity and eating-related disorders.

Section snippets

The endogenous cannabinoid system

The appetite inducing effects of marijuana (cannabis sativa), particularly for sweet and palatable food, have long known and are well documented in the literature (Cota et al., 2003a). Recent evidence shows now that an endogenous cannabinoid system provides the neuro-anatomical basis for the behavioral effects induced by marijuana and its derivatives, and that this system is also involved in several physiological processes relevant for memory, pain, motor activity and energy balance, among

The opioid system

Opiates have been used as analgesics for centuries, as first reported by the Greek physician Galen. The prototype, opium, is derived from Papaver somniferum, commonly known as the poppy. In the 1970s, several laboratories reported that animals also synthesize opiate-like compounds, now referred to as the endogenous opioids (Bodnar and Klein, 2004). These neuroregulatory peptides are synthesized in the central nervous system and the periphery and impact both physiology and behavior. They affect

The current model of the central regulation of energy homeostasis

The involvement of various hypothalamic regions in the regulation of energy homeostasis derives from degeneration studies in the 1940s and 1950s: destruction of the hypothalamic ventromedial (VMN), paraventricular (PVN) and dorsomedial (DMN) nuclei induced hyperphagia (reviewed in Horvath and Diano, 2004). In contrast, discrete lesions placed in the lateral hypothalamus (LH) reduced food intake (reviewed in Horvath and Diano, 2004). While these approaches may be considered crude by today's

The circuits of reward and the regulation of feeding behavior

While the neuronal circuitry that ensures sufficient caloric intake by supporting the orexigenic drive is mainly represented by the hypothalamus and the brainstem (see for review (Flier, 2004, Grill and Kaplan, 2002, Kalra et al., 1999, Seeley and Woods, 2003) and previous chapter), the “liking” (pleasure/palatability) and “wanting” (appetite/incentive motivation) associated with the increased availability and variety of food are processed in the corticolimbic structures, a series of

Functional neuroanatomy of the cannabinoid–opioid cross-talk

An increasing number of studies indicate that cannabinoids and opioids in part use identical mechanisms to modulate physiological processes, including nociception, motor behavior, reward and appetite (Manzanares et al., 1999, Navarro et al., 2001). Consistent with this observation, distribution of CB1 receptors, opioid receptors and of their endogenous ligands has been found to be very similar within brain areas of reward circuitry (Herkenham et al., 1991, Mansour et al., 1995).

CB1 receptors

Cannabinoid antagonists in the therapy of obesity

As described in the previous sections of this review, the endocannabinoid system is clearly involved in the homeostatic control of food intake and modulates food craving, thus representing a valid target for the treatment of obesity and eating-related disorders. Recent studies have evaluated the long-term efficacy of CB1 blockade on food intake and body weight in animal models, showing the ability of CB1 antagonists to interfere with peripheral and metabolic processes involved in the regulation

Opioid antagonists in the therapy of obesity

Based on the animal studies previously reported, it is conceivable to hypothesize that opioid antagonists should be useful for the therapy of obesity. There have been a number of controlled trials with intravenous naloxone, oral naltrexone and oral nalmefene on short-term food intake in healthy, normal weight, humans (reviewed in Yeomans and Gray, 2002). The number of subjects in these trials was relatively small ranging from 7 to 26, and few of the studies tested both women and men. While

Final synopsis and future perspectives: is eating an addiction and should be treated as such?

Food intake and energy expenditure are greatly influenced by the central nervous system. It is reasonable to suggest that the homeostatic regulation of energy metabolism, which is to support survival, is governed by hypothalamic and brainstem regions. Components of both the cannabinoid and opioid systems are present and participate in the regulation of homeostatic centers of energy metabolism, including the hypothalamus (see Fig. 3). Not considering the role of the endocannabinoid system in the

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