Opioid peptides and the control of human ingestive behaviour

A variety of evidence suggests that endogenous opioid peptides play a role in the short-term control of eating. More recently, opioid receptor antagonists like naltrexone have been approved as a treatment for alcohol dependence. Here we review the evidence for a role of opioid peptides in both normal and abnormal eating and drinking behaviours and in particular try to identify the nature of the role of opioids in these behaviours. Particular attention is paid to the idea that opioid reward processes may be involved both in the short-term control of eating and hedonic aspects of alcohol consumption, and parallels are drawn between the effects of opiate antagonists on food pleasantness and the experience of drinking alcohol. The review also explores the extent to which data from studies using opiate antagonists and agonists provide evidence for a direct role of endogenous opioids in the control of ingestive behaviour, or alternatively whether these data may be better explained through non-specific effects such as the nausea commonly reported following administration of opiate antagonists. The review concludes that the present data suggests a single opioid mechanism is unlikely to explain all aspects of ingestive behaviour, but also concludes that opioid-mediated reward mechanisms play an important control in hedonic aspects of ingestion. The review also highlights the need for further empirical work in order to elucidate further the role of opioid peptides in human ingestive behaviour.     

Opioids and consummatory behavior

Since the second decade of this century it has been known that opiates can influence ingestive behaviors. Generally, opioid agents enhance feeding and opioid antagonists decrease feeding. The present paper reviews the responsiveness of different animal species to opiates in relation to ingestive behaviors, the opioid receptors involved in such consummatory behaviors, the site of action of opioid modulation of feeding, the role of glucose in opioid induced feeding, and endocrine effects on opioid feeding systems. We emphasize the finding that more than one opioid receptor is involved in the modulation of feeding. A large body of evidence indicates a major role for the dynorphin/alpha-neo-endorphin kappa opioid receptor as one of the receptors involved in feeding modulation. Opioids appear to exert their effect predominantly within the central nervous system, though peripheral effects on taste and gastrointestinal function may play a role in opioid-induced feeding. Although opioid blockade acutely blocks food intake, chronic administration of opiate antagonists to humans and laboratory animals has not proven to be an effective means of decreasing body weight. Chronic opiate administration decreases body weight and autosensitization of beta-endorphin increases body weight. Thus, although it is clear that opioids can effect food intake, it is not clear what effect chronic administration of opioids has no food intake or body weight.     

The opioid system and the social brain: implications for depression and suicide

In the past decade, considerable attention has been drawn to social interactions and behaviors as sources of pleasurable (social reward) and painful (social pain) emotional states. While the role of the opioid system in the regulation of reward and pain processes has long been recognized, it has more recently been investigated and characterized in the specific context of social experiences across several mammalian species. Accordingly, the present narrative review provides a comprehensive summary of studies detailing how the opioid system controls social reward and social pain. From a translational and pathophysiological perspective, we further discuss how opioid-dependent regulation of social behaviors may contribute to depressive illness and suicidal behaviors, and ultimately provide innovative therapeutic opportunities.     

Opioids and food intake: distributed functional neural pathways?

Agonists of the mu, delta, kappa and ORL(1)opioid receptors increase food intake while opioid receptor blockade decreases food intake. The majority of the collected data related to opioids and feeding has led to the speculation that opioids are involved in meal maintenance and orosensory reward; however, some data suggest that opioids may impact feeding associated with energy needs. Based on the wide distribution of CNS opioid receptors and the presence of other neuropeptides in the vicinity of opioidergic pathways, it seems likely that opioids affect multiple feeding systems. For example, opioids in the hindbrain might be involved in both sensory and metabolic aspects of food intake, those in the amygdala in processing of 'emotional' properties of foods, and those in the hypothalamus in energy needs. In this review we present data which support functional diversity of opioids in feeding behavior.     

Role of bombesin-related peptides in the control of food intake

In 1970, Erspamer et al.(1,14)isolated and characterized the tetradecapeptide bombesin (BN) from the skin of amphibian frog Bombina bombina. Subsequently, several BN-like peptides have been identified in mammals, consisting of various forms of gastrin-releasing peptide (GRP) and/or neuromedin B (NMB), together with their distinct receptor subtypes. It has been proposed that BN-related peptides may be released from the gastrointestinal (GI)-tract in response to ingested food, and that they bridge the gut and brain (through neurocrine means) to inhibit further food intake. Conversely, the suppression of release of BN-like peptides at relevant brain nuclei may signal the initiation of a feeding episode. The present review will describe recent pharmacological, molecular, behavioral and physiological experiments, supporting the contention that endogenous BN-related peptides do indeed influence ingestive behaviors. Particular attention is focused on the relationship between these peptides in the peripheral compartment and their impact on central circuits using GRP and/or NMB as transmitters. In addition, however, we will point out various caveats and conundrums that preclude unequivocal conclusions about the precise role(s) of these peptides and their mechanism(s) of action. We conclude that BN-related peptides play an important role in the control of food intake, and may contribute to ingestive disruptions associated with anorexia (anorexia nervosa, AIDS and cancer anorexia), bulimia, obesity and depression. Hence, pharmacological targeting of these systems may be of therapeutic value.     

Ghrelin in the CNS: from hunger to a rewarding and memorable meal?

Ghrelin, the endogenous agonist of the growth hormone secretagogue receptor, has been shown to induce robust feeding responses in numerous experimental models. Although ghrelin comes from both peripheral and central sources, its hyperphagic properties, to a large extent, arise from activity at the brain level. The current review focuses on describing central mechanisms through which this peptide affects consumption. We address the issue of whether ghrelin serves just as a signal of energy needs of the organism or - as suggested by the most recent findings - also affects food intake via other feeding-related mechanisms, including reward and memory. Complexity of ghrelin's role in the regulation of ingestive behavior is discussed by characterizing its influence on consumption, reward and memory as well as by defining its function within the brain circuitry and interplay with other neuropeptides.     

Food restriction dissociates sexual motivation, sexual performance, and the rewarding consequences of copulation in female Syrian hamsters

Animals can switch their behavioral priorities from ingestive to sex behaviors to optimize reproductive success in environments where energy fluctuates. We hypothesized that energy availability differentially affects the appetitive (motivation), consummatory (performance), and learned (rewarding) components of behavior. In Experiment 1, appetitive and consummatory aspects of sex behavior were dissociated in the majority of female Syrian hamsters restricted to 75% of their ad libitum food intake for between 8 and 11 days. Food restriction significantly inhibited vaginal scent marking, decreased the preference for spending time with male hamsters vs. spending time with food, and increased food hoarding with no significant effect on consummatory behaviors such as the incidence of lordosis or food intake. In Experiments 2 and 3, we attempted to use a similar level of food restriction to dissociate sexual appetite from sexual reward. In hamsters, formation of a conditioned place preference (CPP) for copulatory reward is reflected in increased nucleus accumbens (NAc) neural activation, measured as immunocytochemical staining for c-Fos, the protein product of the immediate-early gene, c-fos. In Experiment 2, neural activation increased 1 h after copulation in the NAc, and did not differ significantly between 10-day food-restricted and ad libitum-fed females in any brain area examined. In Experiment 3, females were either food-restricted or fed ad libitum over 8-30 days of conditioning with copulatory stimuli. Food-restricted females showed significantly fewer appetitive behaviors, but no difference in formation of a CPP compared to females fed ad libitum. Together these data are consistent with the idea that mild levels of food restriction that inhibit appetitive behaviors fail to attenuate consummatory behaviors and the rewarding consequences of copulation. Thus, appetitive sex behaviors are, at least partially, neuroanatomically and behaviorally distinct from both consummatory behaviors and copulatory reward.     

An approach to the development of drugs for appetite disorders

This review covers some modern concepts in the development of drugs to treat appetite disorders. Specific attention is paid to the peripheral satiety system and the role of gastrointestinal peptides such as cholecystokinin in the pathogenesis of satiety. Alterations in neuropeptide Y and/or peptide YY are suggested to play a role in the pathophysiology of bulimia. Corticotropin-releasing factor is a putative candidate peptide involved in anorexia nervosa. The serotonin reuptake inhibitors fenfluramine and fluoxetene decrease weight in obese subjects. Endogenous opioids modulate the choice of palatable foods. Anorexia in the old appears to be related to a decrease in opioid feeding drive and an excess of the satiety action of cholecystokinin. Other agents involved in weight regulation include those which alter gastric emptying, increase thermogenesis, or modulate fat cell metabolism. It should be stressed that many neurotransmitters that modulate appetite also alter other behaviors, increasing their propensity to produce side effects.     

Opioid systems and feeding in the slug, Limax maximus: Similarities to and implications for mammalian feeding

Substantial evidence is accumulating to implicate opioid systems in the regulation of behavioral and physiological functions in invertebrates in a manner analogous to that observed in vertebrates. This communication reviews opiate involvement in the mediation of the ingestive behaviors of the terrestrial slug, Limax maximus. The similarities to and implications for opioid modulation of mammalian feeding are considered.     

Peptides as central regulators of feeding

During the past decade there has been an increased awareness of the role peptides play as neuromodulators. In this article we review the available data on peptides as central regulators of food ingestion. We stress the possible problems of non-specific effects. We stress that whereas many peptides decrease feeding after central injection, only two families of peptides have been shown to increase feeding after central injection. These are the opioid family and the pancreatic polypeptide-neuropeptide Y family. The putative role of corticotropin releasing factor as the mediator of norepinephrine and serotonin effects on feeding is discussed.     

Alcoholism and obesity: overlapping neuropeptide pathways?

Ethanol is a caloric compound, and ethanol drinking and food intake are both appetitive and consummatory behaviors. Furthermore, both ethanol and food have rewarding properties. It is therefore possible that overlapping central pathways are involved with uncontrolled eating and excessive ethanol consumption. A growing list of peptides has been shown to regulate food intake and/or energy homeostasis. Peptides such as the melanocortins, corticotropin releasing factor, and cholecystokinin promote reductions of food intake while others such as galanin and neuropeptide Y stimulate feeding. The present review highlights research aimed at determining if ingestive peptides also regulate voluntary ethanol intake, with an emphasis on the melanocortins and neuropeptide Y. It is suggested that research directed at ingestive peptides may expand our understanding of the neurobiological mechanisms that drive ethanol self-administration, and may reveal new therapeutic candidates for treating alcohol abuse and alcoholism.     

Opioid-induced feeding: Localization of sensitive brain sites

These experiments were designed to identify brain sites at which opioids might act to influence ingestive behavior and to determine which opioid receptor types are involved. After food deprivation, rats were given microinjections of naloxone into several brain regions and food intake was measured. Injections into or near the paraventricular (PVN) or ventromedial (VMH) hypothalamic nuclei or the globus pallidus (GP) reduced food intake; injections into the striatum or lateral hypothalamus (LH) were ineffective. A second study examined the ingestive effects of roughly equimolar doses (1.43-1.75 nmol) of dynorphin A (DYN), beta-endorphin (beta-END), and D-Ala2,D-Leu5-enkephalin (DADLE) when injected into 4 different brain regions. Only DYN significantly increased food intake, and this effect was seen only with injections into the PVN and VMH. Beta-END stimulated water intake when injected into the PVN, VMH and GP but not the LH. Further studies indicated that with PVN injections, DYN was effective at a dose as low as 0.47 nmol, and that a higher dose of DADLE (4.39 nmol) did stimulate food intake. These studies support an important role for dynorphin and the kappa opioid receptor in the regulation of feeding and suggest that the opioid regulation of food and water intake can be differentiated both by sites of action and by effective agonists.     

kappa-Opioid receptor signaling and brain reward function

The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administration of drugs of abuse increases the release of dopamine in the striatum and mediates the concomitant release of dynorphin-like peptides in this brain region. The reviewed studies suggest that chronic drug intake leads to an upregulation of the brain dynorphin system in the striatum and in particular in the dorsal part of the striatum/caudate putamen. This might inhibit drug-induced dopamine release and provide protection against the neurotoxic effects of high dopamine levels. After the discontinuation of chronic drug intake these neuroadaptations remain unopposed which has been suggested to contribute to the negative emotional state associated with drug withdrawal and increased drug intake. kappa-Opioid receptor agonists have also been shown to inhibit calcium channels. Calcium channel inhibitors have antidepressant-like effects and inhibit the release of norepinephrine. This might explain that in some studies kappa-opioid receptor agonists attenuate nicotine and opioid withdrawal symptomatology. A better understanding of the role of dynorphins in the regulation of brain reward function might contribute to the development of novel treatments for mood disorders and other disorders that stem from a dysregulation of the brain reward system.     

Orexin neuronal circuitry: role in the regulation of sleep and wakefulness

Orexin A and orexin B were initially identified as endogenous ligands for two orphan G protein-coupled receptors [104]. They were initially recognized as regulators of feeding behavior in view of their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity [104,30,49,107]. Subsequently, the finding that orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wake cycle [22,46,71,95,117]. These peptides activate waking-active monoaminergic and cholinergic neurons in the hypothalamus/brain stem regions to maintain a long, consolidated awake period. Recent studies on efferent and afferent systems of orexin neurons, and phenotypic characterization of genetically modified mice in the orexin system further suggested roles of orexin in the coordination of emotion, energy homeostasis, reward system, and arousal [3,80,106,137]. A link between the limbic system and orexin neurons might be important for increasing vigilance during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states [137]. Recent research has also implicated orexins in reward systems and the mechanisms of drug addiction [13,48,91]. These observations suggest that orexin neurons sense the outer and inner environment of the body, and maintain proper wakefulness of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis.     

Opioid receptor genes inactivated in mice: the highlights

The opioid system controls nociception, stress responses, and addictive behaviors. Exogenous alkaloid opiates and endogenous opioid peptides stimulate mu-, delta- and kappa-opioid receptors, whose activities have long been analyzed by pharmacological tools. Mice lacking opioid receptor and opioid peptide precursor genes have now been produced by gene targeting. Behavioral analysis of mutant animals in the absence of drug has highlighted a distinct role of opioid receptors or peptides in nociception and revealed an important role for delta receptors in emotional behaviors. The examination of responses to drugs has clarified involvement of each receptor as molecular targets for exogenous opiates in vivo. Those data have also demonstrated the critical role of mu-receptor in cannabinoid and alcohol reinforcement and confirmed the involvement of kappa receptor in several dysphoric responses. Ongoing studies therefore help in understanding the molecular basis of opioid-controlled behaviors and will contribute to the development of novel therapeutics for pain, anxiety, and drug abuse.     

Striatal muscarinic receptor antagonism reduces 24-h food intake in association with decreased preproenkephalin gene expression

Cholinergic interneurons of the striatum respond to motivationally relevant stimuli and are involved in appetitive learning. However, there has been relatively little inquiry into the role of striatal acetylcholine in food motivation. Here we show in rats that a single infusion of the muscarinic receptor antagonist scopolamine (0, 5.0 or 10.0 microg/0.5 microL bilaterally) potently reduced 24-h food intake following injections into either the ventral or dorsal striatum, without affecting water intake. Furthermore, muscarinic receptor blockade induced reliable and widespread reductions in striatal preproenkephalin, but not preprodynorphin, mRNA expression. These data suggest a novel role for striatal acetylcholine in modulating feeding behavior via its effects on enkephalin gene expression. As prior research indicates a critical role for striatal enkephalin in consummatory behaviors and palatability, we hypothesize that cholinergic interneurons assist in translating hypothalamic energy state signals into food-directed behaviors via their regulation of striatal opioid peptides.     

Specific Plasticity Loci and Their Synergism Mediate Operant Conditioning

Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of OC plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia, in vivo and in vitro appetitive OC increases neuronal excitability and electrical coupling among several neurons leading to an increase in expression of ingestive behavior. Here, we used the in vitro analog of OC to investigate whether OC reduces the excitability of a neuron, B4, whose inhibitory connections decrease expression of ingestive behavior. We found OC decreased the excitability of B4. This change appeared intrinsic to B4 because it could be replicated with an analog of OC in isolated cultures of B4 neurons. In addition to changes in B4 excitability, OC decreased the strength of B4''s inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the excitability of another neuron critical for feeding behavior, B8, or the B4-to-B8 inhibitory connection. A conductance-based circuit model indicated that reducing the B4-to-B51 synapse, or increasing B51 excitability, mediated the OC phenotype more effectively than did decreasing B4 excitability. We combined these modifications to examine whether they could act synergistically. Combinations including B51 synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC and that some neurons are well suited to work synergistically with plasticity in other loci.SIGNIFICANCE STATEMENT The ways in which synergism of diverse plasticity loci mediate the change in motor patterns in operant conditioning (OC) are poorly understood. Here, we found that OC was in part mediated by decreasing the intrinsic excitability of a critical neuron of Aplysia feeding behavior, and specifically reducing the strength of one of its inhibitory connections that targets a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in Aplysia is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors.     

Genes, hormones, and circuits: an integrative approach to study the evolution of social behavior

Tremendous progress has been made in our understanding of the ultimate and proximate mechanisms underlying social behavior, yet an integrative evolutionary analysis of its underpinnings has been difficult. In this review, we propose that modern genomic approaches can facilitate such studies by integrating four approaches to brain and behavior studies: (1) animals face many challenges and opportunities that are ecologically and socially equivalent across species; (2) they respond with species-specific, yet quantifiable and comparable approach and avoidance behaviors; (3) these behaviors in turn are regulated by gene modules and neurochemical codes; and (4) these behaviors are governed by brain circuits such as the mesolimbic reward system and the social behavior network. For each approach, we discuss genomic and other studies that have shed light on various aspects of social behavior and its underpinnings and suggest promising avenues for future research into the evolution of neuroethological systems.     

Peptides for calling? An immunohistochemical study of the avian n. intercollicularis.

We used two phylogenetically distant avian species (dark-eyed junco, hyemalis, Passeriformes; domestic pigeon, Columba livia, Columbiformes) to determine the immunocytochemical distribution of opioid (leucine-enkephalin, dynorphin B) and non-opioid (adrenocorticotropic hormone) peptides in the n. intercollicularis (ICo), a midbrain region which plays a central role in the control of vocalizations. We found that, in both species, the peptides under study are present as fibers and terminal-like structures, and are similarly distributed. The n. dorsomedialis intercollicularis division contains much less immunoreactivity than the rest of the ICo. Based on this and previous studies, we propose that opioid peptides, possibly transported from the preoptic and hypothalamic regions of the diencephalon to the ICo, regulate vocal behavior by altering respiratory function rather than syringeal mechanisms.     

Central non-opioid physiological and pathophysiological effects of dynorphin A and related peptides.

Dynorphin A (Dyn A) and related opioid peptides derived from prodynorphin possess a high affinity for kappa opioid receptors, but they also bind to other opioid receptors (mu and delta) as well as to some non-opioid receptor sites. Although the physiological role of these peptides is not well established, recent experimental data pinpoint their particular involvement in physiological and pathophysiological conditions that relate to algesia, spinal cord injury and epilepsy. In this paper, we review data which support the concept that the non-opioid behavioral effects of Dyn A and related endogenous peptides which are observed under these conditions are physiologically and pathophysiologically relevant.