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Minireview: Characterization of Influence of Central Nociceptin/Orphanin FQ on Consummatory Behavior

Minnesota Obesity Center, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417; and University of Minnesota, Department of Psychiatry, Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: Allen S. Levine, Ph.D., Veterans Affairs Medical Center, Research Service (151), One Veterans Drive, Minneapolis, Minnesota 55417. E-mail: allenl{at}umn.edu.

	Abstract

Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

 
Nociceptin/orphanin FQ (N/OFQ), a peptide closely related to dynorphin A, is the endogenous agonist of the NOP receptor that moderately increases food intake under various conditions. Its orexigenic properties are mediated by the brain circuitry. In the present review, we focus on discussing the nature of hyperphagic effects of N/OFQ with special emphasis on its function within feeding-related neural networks. Although some of N/OFQ’s orexigenic effects resemble those induced by opioids, reward-dependent feeding appears to be affected in a different manner by agonists of the NOP and classical opioid receptors. Also, data suggest that N/OFQ may not only promote feeding initiation, but rather its role may be to inhibit signaling responsible for inhibition of consummatory behavior. Central systems involved in termination of feeding that seem to be influenced by N/OFQ encompass oxytocin, -MSH, and CRH.

	Nociceptin/Orphanin FQ (N/OFQ): General Overview

Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

 
Elaborate physiological mechanisms control feeding behavior, including those dependent on interplay between neuropeptidergic pathways. Because consummatory behavior relies on many factors including motivation, energy status, reward, stress, and digestion, numerous neuropeptides that affect each of these processes have been found to be involved in feeding as well.

Importantly, a single neuropeptide does not act alone in the process of food intake regulation; instead, a widely distributed neural network that hosts a variety of peptides appears to determine the feeding status of the organism. Via the organization of this circuitry, neuropeptides interact with one another, for example by affecting each other’s release or by reaching the same target cells.

In this review, we will focus on the feeding effects of N/OFQ, a peptide structurally related to the opioid family. We will also discuss the known interactions of this novel peptide with other neuropeptides involved in the neural network controlling feeding behavior.

In 1995, Meunier et al. (1) isolated a 17-amino-acid molecule that, similarly to opioid receptor agonists, produced antinociceptive effects. It was named nociceptin because of its ability to lower the perception threshold for painful stimuli. The substance was described simultaneously by Reinscheid et al. (2), who referred to it as orphanin FQ, an endogenous ligand of the orphan G_i/G_o-coupled opioid receptor-like 1 receptor, which is currently termed the opioid N/OFQ receptor (NOP).

N/OFQ and classical opioids—in particular, dynorphin A—exhibit high levels of homology (over 60%) (1). The NOP and receptor share a significant degree of similarity as well (3). Importantly, N/OFQ does not bind to the , µ, or receptors; and opioid ligands do not serve as agonists of the NOP (4). The phenylalanine residue instead of tyrosine, characteristic for opioid peptides, present at position 1 of the N/OFQ molecule seems to be the cause for a poor interaction between N/OFQ and the classical opioid receptors (5, 6, 7, 8).

Although N/OFQ and opioids exert their actions through different receptors, they appear to act alike at the cellular level: they activate potassium channels, inhibit calcium channels, and inhibit adenylyl cyclase (9, 10, 11, 12, 13, 14, 15). Also, a variety of brain sites encompass receptors for N/OFQ and for one or more types of opioid peptides (16, 17, 18, 19), which suggests a possibility of a parallel action of these peptidergic systems under some physiological/behavioral circumstances.

Not surprisingly, initial studies on the role of N/OFQ revolved around the assumption that the peptide may serve a similar function to opioids; however, these studies produced conflicting results ranging from opioid-like to anti-opioid effects of N/OFQ (e.g. Refs.20, 21, 22). Mechanisms and processes shown to be influenced by the NOP ligand thus far include nociception (23), neuroendocrine control (24), water-electrolyte balance (25), sexual behavior (26), learning and memory (27, 28), cardiovascular functions (29), and locomotion (30).

In 1996, Pomonis et al. (20) showed for the first time that N/OFQ injected into the lateral cerebral ventricle [intracerebroventricularly (ICV)] induced a short-lived hyperphagia in sated rats. Subsequent studies revealed that only direct administration of this substance into the brain causes changes in feeding; peripheral N/OFQ does not affect consummatory behavior (20, 31, 32).

Although N/OFQ was found to alter feeding activity, it did not change drinking behavior. In fact, N/OFQ-treated rats exhibit low food intake-associated drinking, which seems counterintuitive considering evidence of diuretic actions of this endogenous NOP receptor agonist (33).

Analyses of organization of the central N/OFQ system, i.e. distribution of N/OFQ-containing neuronal elements and of the NOP receptor in the brain, provided a solid neuroanatomical foundation supporting the notion that N/OFQ regulates food intake through central mechanisms (see Table 1). Based on the presence of N/OFQ-positive fiber terminals, N/OFQ is synthesized and released in several brain areas involved in the control of ingestive behavior, including the striatum, hypothalamus (lateral hypothalamus, and paraventricular (PVN), supraoptic (SON), arcuate (ARC), dorsomedial, and ventromedial nuclei), and brain stem (nucleus of the solitary tract and parabrachial nucleus) (18). In addition, these feeding-related structures contain the NOP receptor (19). Mapping c-Fos immunoreactivity (IR) after administration of this peptide was employed to identify regions involved in mediating effects of N/OFQ. c-Fos protein is expressed rapidly in stimulated neurons, where it serves to promote transcription events; it has been shown to be a reproducible marker of neuronal activation (34). A difference in Fos IR between saline- and N/OFQ-treated animals confirmed the significance of the nucleus of the solitary tract (NTS), PVN, SON, and central nucleus of the amygdala (CeA) in mediating the action of this peptide, and pointed at the lateral septal and habenular nuclei as potentially important in this process (35).

	Do N/OFQ and Classical Opioids Act Alike in Feeding Regulation?

Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

It has been shown that a feeding response to ICV N/OFQ in sated rats occurs relatively soon, within 8–19 min, after injection; hyperphagic effects can be observed primarily during the first hour post injection (20). Latency of a feeding response to N/OFQ, in agreement with data showing that orexigenic doses of this peptide evoke mild hypolocomotion, is also comparable to that observed following opioid injections (36).

There is also a possibility that, similarly to opioid peptides, N/OFQ may affect feeding not only by inducing this behavior, but also by prolonging it. We found that ICV administration of N/OFQ increases food intake in fooddeprived rats (38), however, at relatively a relatively high dose (10 nmol) compared with studies with sated rats (1–3 nmol) (e.g. Refs.20 , 39 , and 40). Central injection of this peptide increases feeding in sated rats with a very short latency period, whereas N/OFQ only increased feeding in deprived animals during the second hour of the study. Rodi et al. (41) reported that ICV N/OFQ failed to increase food intake in overnight-deprived rats. However, their dose of approximately 2.2 nmol was considerably lower that the dose we found would increase deprivation-induced feeding (10 nmol). Our results suggest that N/OFQ may maintain feeding, which leads to a longer meal; however, this hypothesis has to be corroborated by additional evidence, especially considering the contradictory finding of Rodi et al. (41).

The hypothesis of N/OFQ’s involvement in prolongation of a meal is in agreement with previously published data suggesting that opioids are involved with the maintenance of feeding (42, 43, 44). It also appears to be consistent with emerging evidence that suggests that N/OFQ may inhibit central signaling responsible for termination of consumption (this issue will be discussed in detail in the section entitled Does N/OFQ Affect Neural Systems Involved in the Process of Feeding Termination?).

Furthermore, conditioned taste aversion experiments revealed that pretreating rats with either N/OFQ or agonists of opioid receptors before injection of an aversive agent, lithium chloride, inhibited the development of the conditioned taste aversion (35). In this study, N/OFQ was as effective at promoting antiaversive effects as were the ligands of classical opioid receptors.

Finally, similar changes in c-Fos IR in some feeding-related brain areas can be detected following administration of N/OFQ and opioids/opiates (35, 46). Noteworthy, regions such as the NTS, CeA, SON, and PVN appear to integrate N/OFQ- and opioid-mediated information. Essential elements of the N/OFQ and opioid systems overlap to a certain degree in these areas (16, 18, 19, 47). For example, the NTS encompasses N/OFQ neurons, and µ receptors, as well as dynorphin- and ß-endorphin-containing fibers (48). In addition, the NOP, µ and receptors, N/OFQ neurons, as well as prodynorphin and proopiomelanocortin fibers, are all abundant in the CeA. The PVN and SON receive N/OFQ and opioidergic innervation; the opioid receptor-like 1 receptor as well as and µ receptors are expressed in these areas (17, 18, 19, 48). The fact that some components of the opioid and N/OFQ systems overlap in these feeding-related regions suggests that N/OFQ and opioids may target (to some degree) the same neuronal populations and/or may be part of the same pathway(s). Thus, it may explain sensitivity of N/OFQ-induced feeding to opioid antagonists; and it may also account for a parallel orexigenic action of N/OFQ and opioids under various conditions (20, 32, 49).

Although the above-mentioned findings appeared to support the notion of opioid-like influence of N/OFQ on feeding, evidence related to N/OFQ and "rewarding" aspects of food intake began to emerge that indicated a much greater complexity of this issue.

One of the most characteristic and well-described functions of opioid peptides is the mediation of palatability/reward-dependent consumption (37). For example, it has been shown that genetic elimination of opioid receptors leads to a lower saccharin preference in CXBK mice compared with wild-type animals (50). Dynorphin A and prodynorphin mRNA levels within the hypothalamus are higher in rats having a long-term access to a palatable diet rich in fat and sucrose (51). Blockade of opioid receptors decreases intake of attractive foods and solutions—especially those high in sucrose or fat—more readily than ingestants of neutral or nonpreferred flavors (52, 53, 54). Alternately, opioid receptor agonists are particularly effective in increasing intake of palatable diets (55, 56, 57).

The few experiments published thus far on the effects of N/OFQ on hedonic aspects of ingestive behavior suggest that this peptide does not mediate feeding-associated reward. As discussed above, blockade of opioid receptors decreases intake of palatable foods and solutions, especially those high in sucrose or fat, more readily than ingestion of nonpreferred/bland flavors. It has been reported that ICV administration of N/OFQ, in contrast to opioids, does not increase intake of the highly palatable sucrose solution available 30 min/d to rats that have food and water available ad libitum (36). Moreover, ICV N/OFQ reduces intake of ethanol in alcohol-preferring rats—an effect similar to that evoked by classical opioid receptor antagonists (58, 59). Unlike morphine and other opioid ligands, injection of N/OFQ, in rats that had long-term ad libitum access to both high-carbohydrate (sweet) food and high-fat food does not increase consumption of a favored diet; instead, it elevates intake of both diets primarily in fat-preferring rats (39).

In addition, a recent study by Nicholson et al. (60) demonstrated that the presence of circulating corticosterone and central glucocorticoid receptors necessary in the mediation of N/OFQ-induced hyperphagia. Those authors found that ICV administration of 0.64–5 nmol N/OFQ dose-dependently elevated plasma corticosterone levels within 30 min of injection. In adrenalectomized animals, N/OFQ did not generate feeding; orexigenic action of the NOP receptor agonist was restored following corticosterone replacement. Previous studies have shown that, in contrast to N/OFQ, agonists of classical opioid receptors, such as ethylketocyclazocine and butorphanol tartrate, produce a more robust consummatory response in adrenalectomized rats than in intact animals (61). In fact, surgical removal of the adrenals suppressed the anorexigenic action of an opioid receptor antagonist, naloxone. It should be noted, however, that some authors reported that corticosterone, under some conditions, may also promote hyperphagic effects of certain opioid receptor agonists (62).

In sum, currently available data present a possibility that there is a certain extent of interplay between N/OFQ and opioids in food intake regulation: similarities in feeding responses evoked by these peptides under some circumstances, reversal of N/OFQ-induced hyperphagia by naloxone or naltrexone, and some extent of overlap in neuroanatomical distribution of these neuropeptidergic systems allow us to formulate such a hypothesis. However, the fact that N/OFQ and opioids appear to play different roles in hedonic aspects of consumption and that these peptides may rely on corticosterone-dependent feeding processes in an opposite manner suggests that N/OFQ’s orexigenic effects do not stem solely from the interaction between the N/OFQ and opioid systems.

	Does N/OFQ Affect Neural Systems Involved in the Process of Feeding Termination?

Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

 
Although initial research on the role of N/OFQ in feeding control focused on the ability of the peptide to initiate food intake, evidence suggests that N/OFQ may play a special role in the process of inhibiting central signaling responsible for termination of consummatory behavior. Studies have shown that ICV N/OFQ supports prolongation of a meal in refed rats. Conversely, synthetic antagonists of the NOP receptor reduce the amount of consumed food and shorten duration of a meal (33, 63). As stated above, we showed the ability of N/OFQ to diminish anorexigenic and aversive effects of a toxin, lithium chloride.

In a recent study, Rodi et al. (41) evaluated the effect of food deprivation on mRNA levels of the precursor for N/OFQ, prepro-N/OFQ, and the NOP receptor. These investigators found a reduction in NOP mRNA in the PVN, LH, and CeA of food-restricted rats. Deprived animals exhibited lower pro-N/OFQ mRNA levels in the CeA. Although these data suggest the involvement of the N/OFQ system in feeding control, a decrease in prepro-N/OFQ and NOP mRNA levels could appear inconsistent with orexigenic role of N/OFQ. Taking into account that at the cellular level N/OFQ exerts an inhibitory influence on neuronal activation (2), a hypothesis was put forth that orexigenic properties of this peptide stem from its inhibitory effect on activity of brain pathways responsible for termination of feeding. Following food deprivation, these neurons may be less active and, thus, the N/OFQ-NOP system, which controls them, may also be regulated at a lower level. It should also be noted that food deprivation/restriction also results in a decrease in gene expression of opioid pre-propeptides in the ARC of the hypothalamus (64).

In our laboratory, we have recently identified two possible neural targets for the inhibitory action of N/OFQ. One of those is the -MSH system; the other, the oxytocin (OT) system (65, 66). Importantly, both OT and -MSH promote termination of consummatory behavior via central circuitry. -MSH seems to play a prominent role as a neuropeptide promoting satiety-induced termination of feeding (67). OT, which is released at the end of a meal as a result of gastric distention and increase in plasma osmolality, also appears to be involved in consumption-related protective mechanisms: OT neurons are activated when sickness/malaise develops after the ingestion of toxic tastants (68, 69). In our studies, we found that N/OFQ injection diminishes feeding-induced activation (defined through immunostaining for c-Fos) of OT neurons in the PVN and -MSH cells in the ARC (65, 66). In addition, N/OFQ pretreatment decreases the percentage of c-Fos-positive OT and vasopressin neurons in rats injected with an aversive (thus, also anorexigenic) agent (35). Obviously, it cannot be determined at this point whether N/OFQ acted directly at these cells; however, we can conclude that it did at least affect pathways that encompass these peptides. These data strongly support the hypothesis that orexigenic properties of N/OFQ stem from this peptide’s inhibitory influence on activity of neural systems that promote termination of feeding. In support of such notion, there is evidence suggesting that N/OFQ may increase food intake by suppressing activity of the part of the NTS-PVN pathway responsible for feeding termination. It has been found that in each case when N/OFQ alleviated the effects of stimuli that promote a decrease in consummatory behavior (such as satiation or injection of an anorexigenic/aversive agent), it also lead to a decline in activation of the NTS and PVN.

A significant body of evidence points to an interaction between the N/OFQ and CRH systems in control of ingestive behavior. In a series of studies, Ciccocioppo et al. (70) evaluated the role of N/OFQ on stress-related feeding. They found that ICV pretreatment of 0.1–2.0 µg N/OFQ blocked hypophagia induced by footshock stress or ICV CRH injection. Administration of the synthetic NOP receptor agonist, Ro 64–6198, also inhibited the anorectic influence of stress and CRH (71). Recently, Ciccocioppo et al. (72) studied the effect of N/OFQ injected into specific brain sites on CRH-induced anorexia. They found that the anorexigenic action of 200 ng of ICV CRH could be reversed by pretreatment with 25–500 ng N/OFQ injected into the bed nucleus of the stria terminalis (BNST) but not into the CeA, locus coeruleus, hypothalamic ventromedial nucleus, PVN, or dorsal raphe. Importantly, microinjection of 50–100 ng of CRH into the BNST, but not into the CeA or the locus coeruleus, induced marked anorexia in food-deprived rats. Pretreatment with N/OFQ into the BNST also blocked the anorectic action of CRH given in the same area (72). Such data suggest that CRH acting within the BNST mediates hypophagia, and this anorexigenic effect of BNST CRH is prevented by activation of N/OFQ receptors.

	Conclusion

Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

 
N/OFQ, a neuropeptide closely related to the opioid family, induces a mild orexigenic response in a manner somewhat similar to classical opioids. N/OFQ is capable of initiating food and maintaining food intake; however, it does not appear to mediate rewarding properties of consumption. This peptide affects food intake by acting through the central nervous system. Available data suggest that orexigenic properties of N/OFQ stem from its interactions with other feeding-related neuropeptidergic systems (see Fig. 1 for summary). It is likely that N/OFQ inhibits activity of pathways that promote termination of consummatory behavior, such as those that encompass OT, vasopressin, -MSH, and CRH. Also, there is a possibility of disinhibitory influence of this peptide on some neural systems that contain opioids.

View larger version (39K): [in this window] [in a new window]   FIG. 1. Model of presumed interplay between N/OFQ and other feeding-related neuropeptidergic systems. Orexigenic properties of N/OFQ stem from this peptide’s influence on activity of broad and dispersed neural circuitry involved in control of consummatory behavior. Based on available data, it can be hypothesized that N/OFQ inhibits activity of pathways that promote termination of food intake, including those that contain oxytocin, vasopressin, CRH, and -MSH. N/OFQ may also cause a disinhibition of some neural systems that encompass opioid peptides, thus, the ones that promote hyperphagia.

	Footnotes

 
This work was supported by the Department of Veterans Affairs, by the National Institute of Drug Abuse Grant DA-03999, and the National Institutes of Health P30 DK-50456.

Abbreviations: ARC, Arcuate nucleus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; ICV, intracerebroventricularly; IR, immunoreactivity; NOP, opioid N/OFQ receptor; N/OFQ, nociceptin/orphanin FQ; NTS, nucleus of the solitary tract; OT, oxytocin; PVN, paraventricular nucleus of the hypothalamus; SON, supraoptic nucleus.

Received January 7, 2004.

Accepted for publication February 23, 2004.

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Top Abstract Nociceptin/Orphanin FQ (N/OFQ):... Do N/OFQ and Classical... Does N/OFQ Affect Neural... Conclusion References

 

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