Endogenous nociceptin modulates diet preference independent of motivation and reward
Introduction
Changes in dietary patterns, particularly due to increases in readily available foods that are both cheap and have high sugar and fat contents, are believed to be a major factor underlying the increasing prevalence of obesity in Western nations [1]. Amongst the multitude of neurochemical systems involved in regulating feeding behavior, endogenous opioid peptides have been well established [2], [3]. The actions of endogenous opioids may be due to effects on fundamental post-ingestive mechanisms regulating food intake, or effects on higher psychological processes such as motivation and reward (see [2], [4], [5]). For instance, endogenous opioid peptides such as endorphin and enkephalin have well-established roles in mediating the rewarding properties of stimuli such as addictive drugs. Likewise, numerous studies suggest that endogenous opioids mediate the rewarding properties of palatable foods, such as those high in sugar or fat content [6].
Nociceptin (also known as orphanin FQ, abbreviated here to N/OFQ) is a member of the endogenous opioid family (see [7]). Similar to other endogenous opioids, N/OFQ is implicated in rewarded and reinforced behaviors (see [8]). Previous work has led to the hypothesis that N/OFQ generally inhibits reward processes and drug-seeking behavior (see [9] for references), possibly by suppressing activity in neurochemical systems mediating incentive motivation [10] or the hedonic impact of stimuli [11]. Like many neuropeptides, N/OFQ is particularly concentrated in brain areas controlling food intake such as the hypothalamus [12], [13]. When administered intracerebroventricularly (i.c.v.), N/OFQ stimulates food intake [14], [15]. Specifically, it appears that activation of the N/OFQ receptor (termed the “NOP” receptor) initiates and maintains feeding behavior, though a role for N/OFQ in inhibiting processes terminating feeding behavior has also been suggested [16].
Virtually all studies to date have investigated the effects of exogenous N/OFQ on feeding-related behavior. Thus, the purpose of the current study was to seek evidence of a physiological role of endogenous N/OFQ in feeding behavior, particularly in modulating the motivating and rewarding properties of food, by studying NOP receptor KO mice (NOP KO). This is particularly topical as obesity rates are increasing in human populations, and targeting the N/OFQ-NOP receptor system may be beneficial in managing pathological feeding behavior [17]. Thus, we studied NOP KO mice in a battery of behavioral responses to high sucrose or high fat diets (which presumably have different palatabilities) designed to assess these psychological processes. Furthermore, as food deprivation increases the motivation to consume, and the palatability of food [18], many of the responses we studied were compared under free-feeding and food-deprived conditions. We predicted that NOP KO mice would generally consume more of, and prefer palatable diets (i.e. those with high sugar or fat contents) and work harder to obtain them, based on the prediction that such diets would be more rewarding in the absence of endogenous N/OFQ effects [9]. However, we found that NOP KO mice generally consumed less, not more, of high sucrose and high fat diets, though only when food deprived. Furthermore, NOP KO mice did not differ in any behavioral tests aimed at identifying differences in motivation or reward, suggesting that the observed effects were due predominantly to an effect of endogenous N/OFQ on post-ingestive processes.
Section snippets
Animals
Experimental protocols used throughout the study were approved by the institutional review committee and were in accord with NIH ethics guidelines. Adult male wild-type or NOP KO mice (aged 9 to 30 weeks, see specific experiments for details), maintained on a C57BL6 background, were generated by mating heterozygous male and female pairs from a colony maintained in the RIKEN Brain Science Institute animal facility from a previously described NOP KO line [19] kindly provided by Prof. Hiroshi
Experiment 1: Voluntary feeding under food-deprived conditions and drinking behavior under free-feeding conditions
As shown in Fig. 1a, both NOP KO and wild-type mice showed a progressive increase in intake of normal and high sucrose diets when presented on alternating days under non-choice conditions (genotype: F1, 22 = 0.12, p = 0.73; time: F5, 110 = 96.33; p < 0.0001). Notably, abrupt increases in intake were recorded each time normal diet was re-presented, such that intake almost doubled by the third presentation. Both genotypes showed a steady loss of body weight, particularly during the first four days of
Discussion
The purpose of this study was to test the hypothesis that endogenous N/OFQ suppresses the motivating and rewarding properties of foods. We found that mice lacking the influence of endogenous N/OFQ due to genetic deletion of the NOP receptor showed generally lower voluntary intake of solid diets high in sucrose or fat. This is in contrast to drinking of liquid diets such as sucrose solutions or oil (though drinking behavior was only studied here under water-deprived conditions). This effect
Acknowledgements
We thank Ms. Reiko Takahashi for scoring of taste reactivity, Dr. Shuichi Kimura for helpful comments on the study, Dr. Michel Vidal-Naquet for assistance with multidimensional scaling analysis, Dr. Nobuhiko Kojima for providing experimental space and Dr. Hiroshi Takeshima for progenitor mice. This work was supported by the RIKEN Brain Science Institute and a Grant-in-Aid for Scientific Research # 18500256.
References (58)
- et al.
Opioid peptides and the control of human ingestive behaviour
Neurosci Biobehav Rev
(2002) Endogenous opioids and feeding behavior: a 30-year historical perspective
Peptides
(2004)- et al.
Central opioids and consumption of sweet tastants: when reward outweighs homeostasis
Physiol Behav
(2007) - et al.
Effect of nociceptin/orphanin FQ on food intake in rats that differ in diet preference
Pharmacol Biochem Behav
(2002) - et al.
Functional interaction between nociceptin/orphanin FQ and alpha-melanocyte-stimulating hormone in the regulation of feeding
Peptides
(2006) Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns
Neurosci Biobehav Rev
(2000)- et al.
Opioid modulation of taste hedonics within the ventral striatum
Physiol Behav
(2002) - et al.
Pro-nociceptin/orphanin FQ and NOP receptor mRNA levels in the forebrain of food deprived rats
Brain Res
(2002) - et al.
Effect of novel NOP receptor ligands on food intake in rats
Peptides
(2006) - et al.
Feeding induced by food deprivation is differentially reduced by opioid receptor antisense oligodeoxynucleotide probes in rats
Brain Res
(2003)
Opioids and food intake: distributed functional neural pathways?
Neuropeptides
Gastrointestinal effects of intracerebroventricularly injected nociceptin/orphaninFQ in rats
Peptides
Gastric acid secretion stimulated by centrally injected nociceptin in urethane-anesthetized rats
Eur J Pharmacol
The hyperphagic effect of nociceptin/orphanin FQ in rats
Peptides
Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect
Physiol Behav
Effects of social crowding on emotionality and expression of hippocampal nociceptin/orphanin FQ system transcripts in mice
Behav Brain Res
Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene
Behav Brain Res
Orphanin FQ, a novel neuropeptide with anti-stress-like activity
Brain Res
Altered anxiety-related behavior in nociceptin/orphanin FQ receptor gene knockout mice
Peptides
The orphanin FQ/nociceptin knockout mouse: a behavioral model for stress responses
Neuropeptides
Tissue distribution of the opioid receptor-like (ORL1) receptor
Peptides
Neural mechanisms underlying obesity and drug addiction
Physiol Behav
Nutrition transition and its relationship to the development of obesity and related chronic diseases
Obes Rev
Opioids for hedonic experience and dopamine to get ready for it
Psychopharmacology (Berl)
Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding
Psychopharmacology (Berl)
Nociceptin/orphanin FQ: actions within the brain
Neuroscientist
Nociceptin/orphanin FQ, hedonic state and the response to abused drugs
Nihon Shinkei Seishin Yakurigaku Zasshi
Endogenous nociceptin (orphanin FQ) suppresses basal hedonic state and acute reward responses to methamphetamine and ethanol, but facilitates chronic responses
Neuropsychopharmacology
Exogenous, but not endogenous nociceptin modulates mesolimbic dopamine release in mice
J Neurochem
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Current address: Shimojo Implicit Brain Function Project, ERATO, Japan Science and Technology Agency, NTT Atsugi Research and Development Center, Kanagawa 243-0198, Japan.