The role of previous exposure in the appetitive and consummatory effects of orexigenic neuropeptides

The ingestion of foods is comprised of two distinct phases of behavior: appetitive and consummatory. While most food intake paradigms include both phases, the intraoral intake test emphasizes the stereotyped consummatory-phase by infusing a liquid food directly into the oral cavity. Several hypothalamic peptides have been shown to increase intake of chow in standard food intake paradigms and the current experiments sought to test whether these peptides would increase food intake in the intraoral intake paradigm. NPY, melanin-concentrating hormone (MCH) and orexin-A were infused into the third ventricle (i3vt) in a counterbalanced latin-square design just prior to rats getting 0.1M sucrose solution infused via indwelling intraoral catheters and compared it to intake on bottle tests with access to the same sucrose solution. On the first day, each peptide increased intraoral intake relative to saline in the between-subjects comparison. Moreover, intake of sucrose following i3vt saline increased as a function of training. By the final day of the experiment, rats receiving saline consumed as much sucrose as rats receiving NPY, MCH, or orexin-A. This finding was conceptually replicated in the second experiment in which rats drank sucrose freely from a bottle on the home cage. A third experiment directly assessed the role of previous exposure in the sucrose intake induced by NPY. Those results confirm that repeated exposure to sucrose increases baseline intake and attenuates the hyperphagic effect of NPY. These results are consistent with two conclusions: (1) NPY, MCH, and orexin-A increase both appetitive and consummatory-phase ingestive behaviors on initial exposures; (2) repeated training interacts with the effects of these orexigenic peptides.     

Effect of the melanocortin receptor stimulation or inhibition on ethanol intake in alcohol-preferring rats

It has been recently reported that acute intracerebroventricular injection of 1 nmol/rat of the non-selective melanocortin 3 and 4 receptor (MC3/4) agonist MTII reduces ethanol intake in female AA alcohol-preferring rats and alters opioid peptide levels in the ventral tegmental area of rats. To better understand the role of the MC system in the control of ethanol intake, we tested the acute and chronic effects of lateral ventricular (LV) injections of 0.01-1 nmol MTII, of 0.1-1 nmol of the MC3/4R receptor antagonist agouti related peptide (AgRP), and 0.1-0.5 nmol of the MC3/4R receptor antagonist SHU9119 on food, water, and 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats, which spontaneously ingest pharmacologically relevant quantities of ethanol both under short and long term access conditions. The data showed that with 2h/day ethanol access, LV MTII injections reduced intake of food and ethanol intakes. When food, water, and ethanol were available ad libitum and 0.01 nmol MTII was given by daily LV injection, however, ethanol intake was reduced for only the first 2 days, whereas food intake was reduced for all 5 days of treatment. Finally, acute LV injection of neither AgRP nor SHU9119 affected ethanol intake under ad libitum conditions, although both antagonists significantly increased food and water intake. In conclusion, these data fail to support a role for endogenous MC3/4R in the control of spontaneous ethanol intake in the msP rat. MC3/4R agonism, however, reduced ethanol intake in association with reduced food intake, suggesting that MTII might reduce nutrient-related controls of ethanol intake rather than, or in addition to, reward-related controls of ethanol intake.     

Properties of rat melanin-concentrating hormone receptor 1 internalization

Melanin-concentrating hormone (MCH) is a neuropeptide that plays an important role in several physiological processes. It activates two G protein-coupled receptors (GPCRs), MCH1R and MCH2R, of which MCH1R seems to be a key regulator of food intake. By using HEK293T cells stably transfected with Flag-tagged rat MCH1R, we investigated the mechanism underlying the MCH-induced internalization pathway, which is important for the desensitization or regulation of the receptor response. Quantitative analysis by flow cytometry indicated that the rate of MCH1R internalization progressed in a rapid and time-dependent manner during the first 30 min, and was partly inhibited by pretreatment with the selective protein kinase C (PKC) inhibitor Go6850. Overexpression of dominant-negative beta-arrestin-2 (284-409) or dynamin I-K44A significantly prevented MCH-induced internalization of MCH1R, while overexpression of dominant-negative beta-arrestin-1-V53D had no effect. A triple-substituted mutant at Thr317, Ser325 and Thr342 to Ala residue in the C-terminus significantly prevented MCH-induced receptor internalization. Similar extents of internalization prevention were noted with the deletion mutants DeltaThr342 and DeltaGlu346, lacking 11 and 7 residues in the C-terminal tail, respectively. Our data suggest that MCH1R undergoes rapid MCH-induced internalization through a PKC-, beta-arrestin-2- and dynamin I-dependent pathway and that a portion of the C-terminal tail plays an important role in the internalization process.     

Interaction Between Oxytocin and Opioidergic System on Food Intake Regulation in Neonatal Layer Type Chicken

The aim of the current study was to determine possible interaction of central oxytocin and opioidergic system on food intake regulation in neonatal layer-type chicken. In experiment 1, FD₃ chicken ICV injected with control solution, oxytocin (10 µg), β-FNA (µ receptor antagonist, 5 µg) and oxytocin (10 µg)?+?β-FNA were injected. Experiments 2–6 were similar to experiments 1, except chicken injected with nor-BNI (κ receptor antagonist, 5 µg), NTI (δ receptor antagonist, 5 µg), DAMGO (µ receptor agonist, 62.25 pmol), U-50488H (κ receptor agonist, 10 nmol), DPDPE (δ receptor agonist, 20 pmol) instead of β-FNA. In experiment 7, control solution, DAMGO (125 pmol), d(CH2)5Tyr(Me)-[Orn8]-vasotocin (oxytocin antagonist, 5 µg) and DAMGO?+?d(CH2)5Tyr(Me)-[Orn8]-vasotocin were ICV injected to FD₃ chicken. Experiments 8 and 9 were similar to experiments 7, except chicken injected with U-50488H (30 nmol) and DPDPE (40 pmol) instead of DAMGO. Then, cumulative food intake was recorded at 30, 60 and 120 min after injection. According to the results, ICV injection of the oxytocin (10 µg) significantly decreased food intake compared to control group (P?<?0.05). Co-injection of the oxytocin?+?β-FNA and oxytocin?+?U-50488H significantly decreased hypophagic effect of the oxytocin (P?<?0.05). While, co-injection of the oxytocin?+?nor-BNI or oxytocin?+?DAMGO significantly amplified hypophagic effect of the oxytocin in chicken (P?<?0.05). In addition, ICV injection of DAMGO (125 pmol) significantly decreased cumulative food intake compared to control group (P?<?0.05). However, co-addministration of the DAMGO?+?(CH2)5Tyr(Me)-[Orn8]-vasotocin significantly decreased hypophagic effect of the DAMGO (P?<?0.05) in chicken. These results suggested there are interconnection between oxytocin and opioidergic system on central food intake regulation, which mediates via µ and κ opioidergic receptors in neonatal layer-type chicken.

     

Antinociceptive effects of two deltorphins analogs in the tail-immersion test in rats

The antinociceptive effects of analogs of deltorphins: cyclo(Nδ,Nδ-carbonyl-d-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) after intracerebroventricular (i.c.v.) administration were investigated in the tail-immersion test in rats. Morphine, the most commonly used μ-opioid receptors (MOR) agonist, was employed as a reference compound. The contribution of the MOR, δ-(DOR) and κ-opioid receptors (KOR) in antinociceptive effects of the deltorphins analogs was studies using selective antagonists of these receptors. The results indicated that DK-4 (5, 10 and 20 nmol) and DEL-6 (5, 10 and 20 nmol) were the most effective in alleviating thermal pain at the dose of 20 nmol. The antinociceptive potency of DEL-6 at the dose of 20 nmol was approximately equal but DK-4 at the dose of 20 nmol was less effective than morphine at the dose of 13 nmol. DOR antagonist – naltrindole (NTI, 5 nmol) very strongly and, to the lower extent MOR antagonist – β-funaltrexamine (β-FNA, 5 nmol), inhibited antinociceptive effect of DK-4 (20 nmol). In turn, β-FNA was more potent than NTI in inhibition of the antinociceptive effects of DEL-6. Co-administration of DEL-6 and morphine at doses of 5 nmol, which do not produce measurable antinociception, generated additive antinociceptive effect. Chronic intraperitoneal (i.p.) injection of morphine (9 days) displayed a marked analgesic tolerance to the challenge dose of morphine and a slight cross-tolerance to challenge doses of DEL-6 and DK-4, given i.c.v. These findings indicate that the new deltorphin analogs recruit DOR and MOR to attenuate the nociceptive response to acute thermal stimuli.     

Stimulation of food intake following opioid microinjection into the nucleus accumbens septi in rats

The involvement of opioid peptides in the regulation of food intake has been postulated. However, it is not known how they are involved in this regulation and which brain region is responsible for the mediation of their effects. We studied the effect of a microinjection of opioid agonists and antagonists into the nucleus accumbens septi (NAS) on the food intake in rats, as this area is known to be important for motivation. Male Wistar rats were implanted stereotaxically with guide cannulae. Rats were not allowed food prior to drug treatment and solutions (1 microliter) were microinjected bilaterally. Food intake was measured throughout a 2 hr period after the drug injection. Infusions into the NAS of 2, 5 and 10 nmol of morphine, D-ala2, D-Leu5-enkephalin (DADLE), and beta-endorphin (beta E), or of 5 and 10 nmol of alpha-neoendorphin (ANEO) induced a dose-dependent increase in the food intake. Dynorphin (DYN) also increased the food intake, but only at a 10 nmol dose. The new, highly selective delta agonist D-Pen2,5-enkephalin (DPDPE) induced a dose-dependent increase in the food intake. Naloxone in doses of 2 and 10 nmol antagonized the increased food intake induced by morphine, beta E, ANEO and DYN in a dose-dependent manner, but only partly antagonized the effect of DADLE on the food intake. The selective mu-receptor antagonist beta-funaltrexamine (beta-FNA), in a dose of 5 nmol completely blocked the increase in the food intake induced by morphine but not by DADLE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential role of the opioid μ and δ receptors in the activation of prolactin (PRL) and growth hormone (GH) secretion by morphine in the male rat

Administration of naloxazone (50 mg/kg i.v.), an irreversible, selective and long acting antagonist of the μ₁ subclass of the opioid receptors, strongly reduced stimulation of PRL secretion by morphine (5.0 mg/kg i.v.) injected 24 hours later into conscious, unrestrained rats. In contrast, the effect of morphine on PRL release was unimpaired in rats treated 24 hours beforehand with either the reversible opioid antagonist naloxone (50 mg/kg i.v.), or the vehicle for naloxazone. A complete suppression of the PRL response to morphine (3.0 mg/kg i.v.) was observed in animals given intraventricular (IVT) injection of β-funaltrexamine (β-FNA, 2.5 μg), another selective, irreversible and long acting antagonist of the μ receptors, 24 hours beforehand. Neither naloxazone nor β-FNA had any effect on the activation of GH secretion by morphine, which, however, was conspiciously reduced by ICI 154, 129, a preferential δ receptor antagonist, injected IVT (50 μg) 5 minutes before morphine. It is concluded that the PRL stimulating effect of morphine is mediated by the μ receptors, wherease activation of GH probably involves the δ sites.     

Spinal δ2 but not δ1 opioid receptors are involved in intracereboventricular β-endorphin-induced antinociception in the mouse

The antinociception induced by β-endorphin given intracerebroventricularly (i.c.v.) has been previously demonstrated to be mediated by the release of Met-enkephalin and subsequent stimulation of δ receptors in the spinal cord for antinociception. The present study was designed to determine what type of opioid receptor, δ1 or δ2, in the spinal cord is involved in i.c.v. β-endorphin-induced antinociception. Antinociception was assessed by the tail-flick test in male ICR mice. NTB (0.2–20 nmol) and NTI0 (0.22–2.2 nmol),selective δ2 receptor antagonists, given intrathecally (i.t.) dose-dependently attenuated i.c.v. β-endorphin-induced inhibition of the tail-flick response. On the other hand, BNTX (0.02–2.2 nmol), a selective δ1 receptor antagonist, given i.t., did not block i.c.v. β-endorphin-induced antinociception. The tail-flick inhibition induced by DAMGO, a μ receptor agonist, or U50,488H, a к receptor agonist, was not blocked by i.t. BNTX, NTB or NTI. It is concluded that δ2 but not δ1 receptors in the spinal cord are involved in i.c.v. β-endorphin-induced antinociception.     

Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake

Neurons that synthesize the morphine modulatory peptide neuropeptide FF (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) densely innervate the parabrachial nucleus (PBN), an area implicated in regulating food intake. We analyzed opioid-related actions of NPFF in feeding in adult male Sprague-Dawley rats. Unilateral infusion of 2 nmol/0.5 microl of the mu-opioid receptor agonist [d-Ala2,NMe-Phe4,glycinol5]enkephalin (DAMGO) into the lateral PBN increased 4-h food intake from 0.7 +/- 0.1 to 3.3 +/- 0.3 g. NPFF (1.25-5.0 nmol) prevented this hyperphagic mu-opioidergic action. In rats fed after 4-h deprivation (baseline = 12.3 +/- 0.3 g/2 h), 5 nmol of NPFF did not alter and larger doses (10 and 20 nmol) actually increased food intake (+36, 54%). Twenty nanomoles also elevated intake of freely feeding rats (from 0.7 +/- 0.1 to 5.1 +/- 1.0 g/4 h). The opioid receptor blocker naloxone (10 nmol) antagonized this increase. These data reveal both pro- and anti-opioid actions of NPFF in the PBN to modulate feeding. The mechanisms for the opposite actions of low and high concentrations of this neuropeptide in parabrachial regulation of food intake remain to be determined.     

"Paradoxical" analgesia and aggravated morphine dependence induced by opioid antagonists

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.     

Amylin and insulin interact to reduce food intake in rats.

We investigated the hypothesis that amylin and insulin, hormones co-secreted by pancreatic B-cells in response to a nutrient stimulus, interact to reduce food intake. A paradigm was employed that assessed food intake in adult male rats after bolus intravenous (i.v.) infusion at dark onset. In one experiment, rats received saline or amylin (0.1, 0.5 or 1.0 nmol). All amylin doses significantly suppressed 1 h intake, and although significant decreases in cumulative intake persisted for 2 h after 0.5 and 1.0 nmol, a significant increase of food intake actually occurred relative to saline during the interval from 1 to 2 h post-infusion. In another experiment, rats received saline, 0.25 nmol amylin, 10 mU insulin, or the combination of amylin plus insulin. Neither amylin nor insulin alone significantly changed cumulative food intake at any time point as compared to saline. However, the combination significantly reduced intake relative not only to saline but also to amylin and insulin alone after 1, 2, and 4 hours. These data are consistent with the hypothesis that endogenous amylin and insulin interact to reduce food intake and, ultimately, body weight.     

Effects of melanin-concentrating hormone on licking microstructure and brief-access taste responses

The effects of intracerebroventricular application of melanin-concentrating hormone (MCH) on licking for sucrose, quinine hydrochloride (QHCl), and water solutions were evaluated in two experiments. In experiment 1, rats received 90-min access to sucrose and water solutions after MCH or vehicle microinjection to the third ventricle (3V). MCH increased intake largely through increases in the rate of licking early in the meal and in the mean duration of lick bursts, suggesting an effect on gustatory evaluation. Therefore, in experiment 2, brief access tests were used with a series of sucrose and QHCl concentrations to behaviorally isolate the effects of intracerebroventricular MCH on gustatory evaluation. MCH uniformly increased licking for all sucrose solutions, water, and weak concentrations of QHCl; however, it had no effect on licking for the strongest concentrations of QHCl, which were generally avoided under control conditions. Thus MCH did not produce nonspecific increases in oromotor activity, nor did it change the perceived intensity of the tastants. We conclude that MCH enhanced the gain of responses to normally accepted stimuli at a phase of processing after initial gustatory detection and after the decision to accept or reject the taste stimulus. A comparison of 3V NPY and MCH effects on licking microstructure indicated that these two peptides increased intake via dichotomous behavioral processes; although NPY suppressed measures associated with inhibitory feedback from the gut, MCH appeared instead to enhance measures associated with hedonic taste evaluation.     

Involvement of spinal kappa opioid receptors in the antagonistic effect of dynorphins on morphine antinociception.

The modulatory effects of intrathecally (i.t.) administered dynorphin A(1-17) and dynorphin A(1-13) on morphine antinociception have been studied previously in rats by other investigators. However, both potentiating and attenuating effects have been reported. In this study, the modulatory effects of i.t. administered dynorphin A(1-17) as well as the smaller fragment, dynorphin A(1-8), were studied in mice. In addition, nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist, and naltrindole (NTI), a highly selective delta opioid receptor antagonist, were used to characterize the possible involvement of spinal kappa and delta opioid receptors in the modulatory effects of the dynorphins. Dynorphin A(1-17) and dynorphin A(1-8) administered i.t. at doses that did not alter tail-flick latencies, were both able to antagonize in a dose-dependent manner, the antinociceptive action of s.c. administered morphine sulfate. The antinociceptive ED50 of morphine sulfate was increased 3.9- and 5.3-fold by 0.4 nmol/mouse of dynorphin A(1-17) and dynorphin A(1-8), respectively. Injections of 0.4 and 0.8 nmol/mouse of nor-BNI i.t., but not its inactive enantiomer (+)-1-nor-BNI, inhibited dose-dependently the antagonistic effects of the dynorphins. These doses of nor-BNI alone did not affect the antinociceptive action of morphine sulfate. Intrathecal administration of 5 nmol/mouse of NTI also did not affect the modulatory effects of dynorphins. These observations that dynorphins exert their antagonistic effects on morphine-induced antinociception stereoselectively through spinal kappa opioid receptors may suggest a coupling between spinal kappa and mu opioid receptors.     

An orexigenic role for mu-opioid receptors in the lateral parabrachial nucleus

The pontine parabrachial nucleus (PBN) has been implicated in regulating ingestion and contains opioids that promote feeding elsewhere in the brain. We tested the actions of the selective mu-opioid receptor (mu-OR) agonist [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) in the PBN on feeding in male rats with free access to food. Infusing DAMGO (0.5-4.0 nmol/0.5 microl) into the lateral parabrachial region (LPBN) increased food intake. The hyperphagic effect was anatomically specific to infusions within the LPBN, dose and time related, and selective for ingestion of chow compared with (nonnutritive) kaolin. The nonselective opioid antagonist naloxone (0.1-10.0 nmol intra-PBN) antagonized DAMGO-induced feeding, with complete blockade by 1.0 nmol and no effect on baseline. The highly selective mu-opioid antagonist d-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 1.0 nmol) also prevented this action of DAMGO, but the kappa-antagonist nor-binaltorphimine did not. Naloxone and CTAP (10.0 nmol) decreased intake during scheduled feeding. Thus stimulating mu-ORs in the LPBN increases feeding, whereas antagonizing these sites inhibits feeding. Together, our results implicate mu-ORs in the LPBN in the normal regulation of food intake.     

Hypothalamic ventromedial and arcuate neurons of normal and postnatally overnourished rats differ in their responses to melanin-concentrating hormone

Melanin-concentrating hormone (MCH) is a neuropeptide involved in regulation of food intake and body weight. The study aimed to detect possible differences in responses of hypothalamic ventromedial and arcuate neurons to MCH, depending on the short-term nutritional state (fed versus food-deprived) and on the long-term state in overweight rats due to early postnatal overnutrition. The effect of MCH on a single-unit activity was studied in brain slices of normal and overweight rats. The latter (n=16) were raised till weaning in small litters (SL) of 3 pups compared to 10 pups in control litters (CL) and gained significantly greater body mass. Whereas MCH in effective concentrations in the pico- to nanomolar range could increase or suppress the activity of ventromedial or arcuate neurons studied in male normal fed or food-deprived (24 h) rats, its action became shaped in an unidirectional way in overweight, hyperphagic rats. Medial arcuate neurons (n=25) from hyperphagic rats were predominantly activated by MCH (p<0.05, paired t-test). This effect differed significantly from that induced on neurons (n=27) of control rats. Ventromedial neurons (n=34) of overweight rats were predominantly inhibited. Activation of arcuate neurons may induce feeding in particular through release of neuropeptide Y (NPY). Inhibition of ventromedial neurons may contribute to reduced energy expenditure. The increased expression of one response type to MCH by a neuronal population in overweight, hyperphagic rats might reflect a general mechanism of neurochemical plasticity and also suggest a participation of the peptide in long-term regulation of food intake and body weight in this model of obesity.     

Characterization of MCH-mediated obesity in mice

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitum-fed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.     

Antagonistic effect of somatostatin on corticotropin-releasing factor-induced anorexia in the rat

The effect of somatostatin on corticotropin-releasing factor (CRF)-induced anorexia was examined in rats. Intracerebroventricular (icv) administration of 0.11 nmol and 0.21 nmol ovine CRF significantly suppressed food intake of 24 h-starved rats. Icv administration of 0.31 nmol somatostatin 14 and somatostatin 28 partially reversed suppression of food intake induced by icv injection of 0.21 nmol CRF in 24 h-starved rats. These results suggest that somatostatin may counteract the suppressive effect of CRF on food intake within the central nervous system.     

Neuropeptide K suppresses feeding in the rat

We studied the effects of neuropeptide K (NPK), a 36 amino acid residue peptide of the tachykinin family, on latency to onset of feeding and cumulative 1 and 2 h food intake in three experimental paradigms. Intraperitoneal injection of NPK (1.25 and 3.14 nmol) to food-deprived rats delayed the onset of feeding and significantly decreased the cumulative food intake. Intraperitoneal injection of NPK (1.25 and 3.14 nmol) to water-deprived rats produced no effect on subsequent drinking behavior. Similarly, intraperitoneal injection of NPK (3.14 nmol) 15 min before onset of the dark phase (of the light-dark cycle) significantly delayed the occurrence of ingestive behavior and the cumulative food intake was markedly suppressed. Furthermore, administration of NPK intraperitoneally (0.5-3.14 nmol) 15 min before intraventricular (i.c.v.) injection of neuropeptide Y (NPY 0.47 nmol) to satiated rats significantly suppressed NPY-induced feeding and delayed the onset of ingestive behavior. However, when administered centrally prior to NPY injection, NPK delayed the onset of feeding response only. Collectively, these findings show that NPK can acutely and consistently suppress feeding behavior.     

The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors

It is known that under some conditions the administration of opioid agonists will stimulate food intake. However, the lack of receptor selectivity of some of the agonists which produce this effect leaves open the question of which receptor types are actually involved. In the experiments presented here, rats were given intracerebroventricular injections of Dynorphin 1-17 (DYN), [D-ala2MePhe4,-Gly-ol5]enkephalin (DAGO), and [D-ser2, leu5]enkephalin-thr6 (DSLET); these peptides are thought to be selective agonists at kappa, mu and delta opioid receptors, respectively. All three peptides stimulated food intake in non-deprived rats at doses in the 3-10 nmol range; water intake was also increased in some cases. Generally, DYN stimulated feeding at a lower dose than DAGO or DSLET and the magnitude of the effect tended to be greater. On the other hand, DAGO more consistently increased water intake. In some cases, DYN also caused episodes of "barrel-rolling" and postural abnormalities, whereas DAGO had sedative and/or cataleptic effects. These results are interpreted as an involvement of more than one opioid receptor types in the regulation of appetite, possibly with separate opioid systems contributing to food and water intake.     

Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake

The lateral hypothalamus (LH) has a critical role in the control of feeding and drinking. Melanin-concentrating hormone (MCH) is an orexigenic peptidergic neurotransmitter produced primarily in the LH, and agouti-related protein (AgRP) is an orexigenic peptidergic neurotransmitter produced exclusively in the arcuate (ARC), an area that innervates the LH. We assessed drinking and eating after third ventricular (i3vt) administration of MCH and AgRP. MCH (2.5, 5, and 10 micro g i3vt) significantly increased food as well as water intake over 4 h when administered during either the light or the dark portion of the day-night cycle. When MCH (5 micro g) was administered to rats with access to water but no food, they drank significantly more water than when given the vehicle. AgRP (7 micro g i3vt), on the other hand, increased water intake but only in proportion to food intake during the dark and the light, and water intake was not increased after i3vt AgRP in the absence of food. Hence, in contrast to AgRP, MCH elicits increased water intake independent of food intake. These results are consistent with historical data linking activity of the LH with water as well as food intake.