Effects of butorphanol on feeding and neuropeptide Y in the rat.

Butorphanol ([BT] an opioid receptor agonist/antagonist) is different from other opioid agonists in that a single dose of BT can elicit up to 12 g of chow intake in a satiated rat whereas most opioid agonists induce a mild feeding response (2-3 g). Here, we first examined whether the effectiveness of BT to elicit feeding was affected by dose, method of infusion and possible tachyphylaxis following administration. Secondly, we examined whether BT administration influenced hypothalamic NPY gene expression and peptide levels. A single dose administration of BT (4 mg/kg) significantly increased food intake at 2, 3 and 6 h after administration. However following repeated injections of BT at 4 mg/kg, the cumulative long-term intake of BT-treated rats did not differ from that of controls, indicating that the animals compensate for the increased feeding following BT injection by decreased feeding at a later time. An ascending dose schedule of repeated BT injections resulted in additional feeding. NPY gene expression in the ARC was influenced by how much food had been consumed, but not by BT. The amount of food consumed and the level of NPY mRNA were inversely correlated. This is consistent with NPY's role in normal feeding. BT treatment did not affect either NPY or leptin RIA levels. We conclude that the feeding produced by BT is sensitive to dose and dosing paradigm. Further, its mechanism of action does not appear to be mediated by NPY or leptin pathways.

Naloxone's effect on meal microstructure of sucrose and cornstarch diets.

The opioid receptor antagonist naloxone decreases consumption of high-sucrose diets but does not reduce cornstarch diet intake in energy-restricted rats. Sucrose-fed rats eat at a much higher rate, consuming more food than cornstarch-fed rats. We examined meal microstructure using an automated weighing system in food-restricted rats eating either a high-sucrose or high-cornstarch diet. Sucrose-fed rats exhibited a higher rate of eating during their first meal compared with cornstarch-fed rats (0.34 vs. 0.20 g/min, respectively). However, naloxone did not reduce eating rate in either group. Naloxone decreased the size of the first meal in both diet groups by shortening the length of the meal. Naloxone's anorectic effect was more potent in the sucrose-fed rats. These results indicate that naloxone's heightened anorectic effect on sucrose diet consumption is not "rate dependent." Naloxone's anorectic actions may be modulated by two conditions, the sensory properties of food and the energy state of the animal. Thus the elevated anorectic potency of naloxone in energy-restricted sucrose-fed rats may reflect actions on neural systems that mediate orosensory and/or postingestive signals.

The kappa-opioid antagonist GNTI reduces U50,488-, DAMGO-, and deprivation-induced feeding, but not butorphanol- and neuropeptide Y-induced feeding in rats.

Antagonists selective for either kappa- [e.g. nor-binaltorphimine (nor-BNI)] and mu- (e.g. beta-funaltrexamine) opioid receptors have previously been shown to reduce both kappa- and mu-opioid-induced feeding. In the present studies, the anorectic effects of GNTI, a newly synthesized antagonist selective for kappa-opioid receptors, were studied in rats. GNTI (0.032-0.32 nmol; i.c.v.), administered 15 min prior to food access, reduced feeding induced by the kappa-opioid agonist U50,488 (producing a 70% maximal decrease), the mu-opioid agonist DAMGO (90% maximal decrease), and 24 h acute food deprivation (60% maximal decrease). GNTI did not reduce the orexigenic effects of butorphanol, an agonist that binds to both kappa- and mu-opioid receptors, and neuropeptide Y (NPY). Taken together, these results suggest that GNTI is a potent anorectic agent and opioid antagonist in rats. Like nor-BNI, GNTI reduced feeding induced by both kappa- and mu-opioid agonists. However, unlike nor-BNI, GNTI did not alter the orexigenic effects of butorphanol or NPY. Given the selectivity of GNTI and its effectiveness in several of the present experiments, its potency, and its short duration of action compared to nor-BNI, GNTI may serve to be a useful tool to study behavioral effects mediated by kappa-opioid receptors.

Role of alpha-MSH in the regulation of consummatory behavior: immunohistochemical evidence.

Central injection of alpha-melanocyte-stimulating hormone (alpha-MSH) decreases food intake, suggesting a role for this peptide in the mediation of satiety. Inasmuch as alpha-MSH also supports the development of taste aversions under certain conditions, the nature of its influence on ingestive behavior, i.e., whether it is related to satiety or aversion, remains unclear. In the present studies, we used immunostaining, including that for c-Fos as a marker of neuronal activation, to further substantiate the physiological role for alpha-MSH in the regulation of consummatory behavior. We found that an increase in activation of alpha-MSH neurons in the arcuate nucleus coincided with meal termination. Administration of powerful aversive agents, LiCl and CuSO(4), did not stimulate alpha-MSH cells but did induce pronounced activation of oxytocin (OT) and vasopressin (VP) neurons, the final components of circuitry mediating aversion. We observed fewer Fos-positive OT/VP neurons after alpha-MSH injection into the lateral ventricle or into the hypothalamic paraventricular nucleus, treatments that cause mild or no aversion, respectively. The degree of activation of OT/VP neurons paralleled the magnitude of aversive response to a given treatment. Our data support the hypothesis that, in the arcuate nucleus, alpha-MSH acts as a satiety mediator independent from aversion-related mechanisms.

Evidence of interactions between melanocortin and opioid systems in regulation of feeding.

The aim of our experiments was to study the presumed functional relationship between the melanocortin and opioid systems in the regulation of food intake. We determined that a non-selective opioid receptor antagonist, naltrexone, at relatively low doses, decreases food intake induced by i.c.v. agouti-related protein (Agrp). We also observed that peripheral injection of naltrexone at a dose known to produce anorexigenic responses induced c-Fos immunoreactivity in significantly more arcuate nucleus alpha-MSH neurons than observed in control animals. The results of our study support the notion that the melanocortin and opioid systems interact in the regulation of food intake. Based on these data we speculate that opioid peptides suppress alpha-MSH-dependent satiety mechanisms; conversely, it is possible that the orexigenic action of Agrp is mediated via opioid dependent circuitry.

Identification of central sites involved in butorphanol-induced feeding in rats.

Butorphanol (BT), a mixed kappa- and mu-opioid receptor agonist, induces vigorous food intake in rats. Peripheral injection of BT seems to increase food intake more effectively than intracerebroventricular administration. To further elucidate the nature of BT's influence on consummatory behavior, we examined which feeding-related brain areas exhibit increased c-Fos immunoreactivity (IR) following subcutaneous injection of 4 mg/kg body weight BT, a dose known to induce a maximal orexigenic response. We also evaluated whether direct administration of BT into the forebrain regions activated by peripheral BT injection affects food intake. Peripheral BT administration induced c-Fos-IR in the hypothalamic paraventricular nucleus (PVN), central nucleus of the amygdala (CeA), and nucleus of the solitary tract (NTS). However, 0.1-30 microg BT infused into the CeA, failed to increase food intake 1, 2, and 4 h after injection. Only the highest dose of BT (30 microg) injected into the PVN increased feeding. These results suggest that the PVN, CeA, and NTS mediate the effects of peripherally-injected BT. The PVN or CeA are probably not the main target sites of immediate BT action.

The effect of [Phe(1)psi(CH(2)-NH)Gly(2)]-nociceptin(1-13)NH(2) on feeding and c-Fos immunoreactivity in selected brain sites.

Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand of the ORL1 receptor. N/OFQ, when administered centrally, stimulates feeding in a fashion similar to other opioids. Intracerebroventricular administration of N/OFQ induces changes in c-Fos immunoreactivity in several feeding-related brain sites. A synthetic pseudopeptide, [Phe(1)iota(CH(2)-NH)Gly(2)]-nociceptin(1-13)-NH(2) (hereafter: [FG]N/OFQ(1-13)NH(2)), has been labeled both as an ORL1 agonist and antagonist. The present study was designed to examine the influence of [FG]N/OFQ(1-13)NH(2) on food intake in rats. We also evaluated c-Fos immunoreactivity in those areas of the brain which have been shown to exhibit altered c-Fos expression upon N/OFQ administration. We found that [FG]N/OFQ(1-13)NH(2) increases food consumption in satiated rats. This effect is short-lasting and can be reversed by the opioid antagonist naloxone. Co-administration of [FG]N/OFQ(1-13)NH(2) does not affect orexigenic response to N/OFQ. Intracerebroventricularly-injected [FG]N/OFQ(1-13)NH(2) induces c-Fos expression in the nucleus of the solitary tract, hypothalamic paraventricular and supraoptic nuclei, central nucleus of amygdala, lateral septal and lateral habenular nuclei-brain areas that have been shown to be activated by N/OFQ. These results support the hypothesis that [FG]N/OFQ(1-13)NH(2) acts as an agonist of ORL1 receptor in vivo.

Nocistatin inhibits food intake in rats.

Nocistatin, a product of the same precursor as nociceptin/orphanin FQ (N/OFQ), has been shown to antagonize effects of N/OFQ. N/OFQ stimulates feeding, most probably by inhibiting activation of neurons containing oxytocin (OT) and vasopressin (VP), peptides considered as satiety factors, and implicated in the development of conditioned taste aversion (CTA). The present study was designed to investigate whether intracerebroventricularly (ICV) injected nocistatin (a) affects deprivation- and N/OFQ-induced feeding, (b) causes CTA, and (c) induces activation of hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, as well as OT and VP neurons present in these regions. C-Fos immunohistochemistry was used as a marker of cellular activation. Nocistatin (1-3 nmol) significantly reduced food intake in deprived rats during the first and second hour post-injection. Doses of 1-3 nmol suppressed N/OFQ-induced feeding. Nocistatin at the highest (3 nmol) dose did not cause CTA. It also did not affect activation of the PVN or SON. In nocistatin-treated animals, the percentage of Fos-positive OT and VP neurons was similar to controls. We conclude that nocistatin antagonizes the influence of N/OFQ on feeding and suppresses deprivation-induced food consumption through mechanisms other than aversion. Nocistatin does not, however, activate the PVN or SON. It does not exert its effects via VP or OT neurons.

ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean zucker rats.

Effects of obesity on gene expression for opioid peptides and neuropeptide-Y (NPY) in the arcuate nucleus (ARC), and on opioid peptides and alpha-melanocyte stimulating hormone (alpha-MSH) in the paraventricular nucleus (PVN) were examined in obese Zucker rats (18 weeks old). Obese Zucker rats are insulin-resistant, diabetic and hyperleptinemic as indicated by high serum glucose, insulin and leptin levels. ARC proOpiomelanocortin (POMC) mRNA levels were significantly lower in the obese relative to lean Zucker rats and ARC proNeuropeptide Y (proNPY) mRNA levels were higher (P<0.05). There were no differences in proDynorphin and proEnkephalin mRNA levels in the ARC (0.05). Obese Zucker rats had lower alpha-MSH and dynorphin A(1-17) peptide levels in the paraventricular nucleus (PVN) (P<0.05), but did not have lower PVN beta-endorphin peptide levels (0.05). The decrease in POMC in the ARC and decrease in alpha-MSH in the PVN seen in the obese Zucker rat in the present study suggest that reduced activity of the melanocortin system in the ARC to PVN pathway may contribute to the related hyperphagia. Reduced activity of the melanocortin system in the ARC to PVN pathway may be due to a disturbance of leptin signaling coupling to POMC.

Differential effects of neuropeptide Y and the mu-agonist DAMGO on 'palatability' vs. 'energy'.

Differential effects of neuropeptide Y (NPY) and mu-opioid DAMGO on 'palatability' vs. 'energy'. A variety of studies suggest that NPY is an important manager of energy metabolism. In contrast, the opioid peptides appear to influence the 'rewarding' aspects of feeding. In the current study, we stimulated feeding by injecting NPY (110 pmol) or the mu-opioid agonist DAMGO (2 nmol) into the paraventricular nucleus of rats. Following injection, rats were given free access to laboratory chow and a 10% sucrose solution. Animals injected with saline derived 10% of their kilocalories from the chow and 90% from the sucrose solution (total kcal/4 h=12.2+/-1. 0). Those rats injected with NPY derived 48% of their energy from chow and 52% from the sucrose solution (total kcal/4 h=24.8+/-1.7). The DAMGO-injected rats derived only 15% of their kilocalories from chow and the remainder from the sucrose solution (total kcal/4 h=23. 0+/-2.3). Thus, while NPY and DAMGO both stimulated energy intake compared to saline controls (P<0.0001), the effect on intake of a palatable dilute energy solution (0.4 kcal/g) vs. a 'bland' laboratory chow (3.95 kcal/g) was different. The results of this study reinforce the notion that NPY has a major effect on energy needs, whereas opioids influence the 'rewarding' characteristics of foods.

STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats.

Effects of streptozotocin (STZ)-induced diabetes and insulin on opioid peptide gene expression were examined in rats. In experiment 1, three groups were administered STZ (75 mg/kg ip single injection). Two groups were killed at either 2 or 4 wk. In the third group, insulin treatment (7.0 IU/kg x 1 day for 3 wk) was initiated 1 wk after STZ injection. STZ induced hyperphagia and reduced weight gain. Insulin decreased food intake and increased body weight relative to diabetes. Proopiomelanocortin (POMC) mRNA in arcuate nucleus (Arc) and pituitary decreased in diabetes and normalized after insulin treatment. Prodynorphin (proDyn) mRNA increased in diabetes and normalized in the pituitary after insulin but not in the Arc. Diabetes did not alter proenkephalin (proEnk) expression in the Arc or pituitary, nor dynorphin A1-17 or beta-endorphin in paraventricular nucleus (PVN). alpha-Melanocyte-stimulating hormone (alpha-MSH) peptide levels were decreased in the PVN and normalized following insulin treatment. Diabetes increased Arc neuropeptide Y mRNA, and insulin suppressed this increase. In experiment 2, insulin (2.5 IU/kg sc) daily for 1 wk in normal rats increased Arc POMC mRNA, but not proDyn and proEnk mRNA. These results suggest that Arc POMC expression and PVN alpha-MSH peptide levels decrease in diabetes. Also, insulin may influence Arc and pituitary POMC activity in neurons that regulate energy metabolism.

Effects of palatability-induced hyperphagia and food restriction on mRNA levels of neuropeptide-Y in the arcuate nucleus.

This study examined the effect of feeding either a bland cornstarch-based diet (BCD) or a highly palatable, high fat diet containing sucrose (HPD) on hypothalamic arcuate nucleus (ARC) gene expression for neuropeptide-Y (NPY). Male Sprague-Dawley rats received either BCD ad libitum, HPD ad libitum, HPD pair-fed to the caloric intake of the BCD, or the HPD at 60% of ad libitum HPD intake for 7 days. Animals receiving the HPD ad libitum consumed more calories and gained more weight than animals receiving the BCD (P<0.001). The HPD did not affect ARC NPY mRNA levels, whether the subjects were allowed to overeat or pair-fed to the BCD (P>0.05). However, feeding the HPD at 60% of ad libitum intake of the HPD, increased NPY mRNA levels in the ARC relative to the other treatments (P<0.01). The present data are consistent with the view that NPY in ARC responds to energy deficits rather than to hyperphagia stimuli related to palatability.

Divergence of the feeding and thermogenic pathways influenced by NPY in the hypothalamic PVN of the rat.

Neuropeptide Y (NPY) injected into the paraventricular nucleus (PVN) increases feeding and decreases brown adipose tissue (BAT) uncoupling protein (UCP) and lipoprotein lipase (LPL) mRNA. Previously we reported that the feeding and BAT effects induced by NPY in the PVN are blocked by 50 microg naltrexone (NTX) in the rostral nucleus of the solitary tract (rNTS). We sought to determine whether the effect of rNTS NTX on PVN NPY-induced alterations in energy metabolism occurred at lower doses of NTX. Male Sprague-Dawley rats were fitted with cannulas into two sites: PVN and rNTS. Feeding response, BAT UCP, and LPL mRNA were measured after injection of 0, 5, 10, and 25 microg NTX in the rNTS +/- 1 microg NPY in the PVN. One-hour feeding response to PVN NPY was significantly and dose dependently decreased by 10 and 25 microg rNTS NTX (-23 and -31%, respectively). However, rNTS NTX did not block the PVN NPY-induced decrease in BAT UCP or LPL mRNA. BAT beta-actin mRNA (as a measure of overall changes in gene expression) was unchanged among treatment groups. These results indicate a possible divergence in the PVN NPY feeding-stimulatory/BAT-inhibitory pathway, such that PVN NPY feeding effects may be routed through the rNTS whereas BAT effects may be due to alterations at another neural site.

Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein.

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.

Effect of peripheral 2-DG on opioid and neuropeptide Y gene expression.

It is well known that 2-Deoxy-d-glucose (2-DG) blocks intracellular utilization of glucose and increases food intake. The aim of the present study was to determine whether administration of 2-DG alters gene expression of the orexigenic peptides, neuropeptide Y (NPY) and endogenous opioids, in the arcuate nucleus of the hypothalamus (ARC). Male Sprague-Dawley rats were injected peripherally (i.p.) with 2-DG (200 or 400 mg/kg body weight) and were sacrificed at 2 or 6 h post injection. Half of the animals were given ad libitum access to food whereas the other half of the animals were food-deprived. 2-DG increased food intake fourfold compared to saline injected animals, but did not affect NPY mRNA levels after 2 h. Messenger RNA levels of ProDynorphin (proDYN), but not pro-opiomelanocortin (POMC) nor proEnkephalin (proENK) were significantly decreased 2 h after 2-DG injection. Administration of 400 mg/kg of 2-DG increased mRNA levels of NPY in the arcuate nucleus after six h, but only in those animals not receiving food.

Lactation decreases mRNA levels of opioid peptides in the arcuate nucleus of the rat.

The state of lactation results in increased food intake to compensate for the increased energy expenditure to produce nutrients supplied to the offspring. In this study, Sprague-Dawley female rats lactating for 10-16 days, and rats 7 days post-lactation were implanted with osmotic minipumps infusing either naltrexone (NTX) (70 microg/h) or saline (0.9%) over a 48 h period. mRNA levels of pro-dynorphin (proDYN), pro-opiomelanocortin (POMC) and pro-enkephalin (proENK) were measured in the arcuate nucleus (ARC) and whole pituitary of both groups. In both saline- and NTX-treated lactating subjects, food intake was higher than in post-lactating subjects (P < 0.01). In post-lactating subjects, NTX decreased food intake by 27% during the infusion period (P < 0.05). There were no significant differences in body weight between the treatment groups; however, naltrexone decreased body weight gain in both lactating and post-lactating subjects. In both saline and NTX-treated lactating subjects, ARC mRNA levels of proDYN, POMC and proENK were significantly decreased compared with the saline or NTX-treated post-lactating subjects (P < 0.01). NTX did not significantly influence gene expression of opioid peptides in the ARC in either the lactating or the post-lactating subjects. Neither the lactation condition nor NTX administration significantly changed mRNA levels of proDYN, POMC or proENK in whole pituitary. Thus, as has been noted in energy-deprived rats, opioid peptide gene expression is decreased in the ARC of lactating rats, a period during which rats have increased energy requirements.

Utilization of a novel model of food reinforced behavior involving neuropeptide Y, insulin, 2-deoxy-d-glucose and naloxone.

The cyclic-ratio schedule methodology exposes animals to an ascending followed by a descending sequence of ratio values over six consecutive cycles. The response functions, obtained by plotting response rates against reinforcement rates at each schedule value, are argued to provide features useful in the evaluation of drug effects on feeding behavior. In the present study the effects of s.c. insulin (5.0IU/kg), i.c.v. neuropeptide Y (NPY) (5.0µg/5.0µl), i.c.v. insulin (0.5mU/5.0µl), i.c.v. 2-deoxyglucose (2-DG) (10.0µg/5.0µl), i.c.v. naloxone (NLX) (50.0µg/5.0µl) in conjunction with i.c.v. NPY (5.0µg/5.0µl), and i.c.v. NLX alone (50.0µg/5.0µl) were assessed, i.c.v. NPY, insulin and 2-DG caused an elevation of the response function obtained by plotting response rates against reinforcement rates but did not affect the slope of the function. This elevation was similar to that observed after increasing the incentive value of the reinforcer (i.e., similar to increasing a 5.0% sucrose concentration reinforcer to 10.0%, and to substituting 45mg sweet food pellets for 45mg grain pellets). S.c. insulin produced no shift in the function from baseline, and i.c.v. NLX blocked the effect of i.c.v. NPY. I.c.v. NLX given alone reduced the slope of the response function, by selectively reducing response rates at the higher schedule values, a shift in the function similar to that observed following an increase in body weight. Since the literature on NPY and insulin would suggest that their effects are mediated through mechanisms associated with internal regulation, these findings were not predicted.

Naltrexone induces arcuate nucleus neuropeptide Y gene expression in the rat.

Neuropeptide Y (NPY) has potent effects on several components of energy metabolism, including increased feeding and decreased brown fat thermogenesis. Negative energy balance, such as food deprivation, increases NPY mRNA in hypothalamic arcuate nucleus (ARC). Naltrexone (NLTX), an opioid receptor antagonist, decreases NPY-induced feeding. We hypothesized that NLTX would alter ARC NPY mRNA and change NPY effects on brown fat. Osmotic minipumps prefilled with either saline or NLTX (70 micrograms/h) were implanted subcutaneously in 32 male Sprague-Dawley rats. One-half of the rats were food deprived and one-half were allowed food ad libitum for 48 h. Food intake was measured at 24 and 48 h. At 48 h, ARC NPY mRNA and brown fat uncoupling protein (UCP) mRNA levels were determined using cDNA probes. Forty-eight-hour food intake was significantly decreased by 24% after NLTX infusion. Food deprivation and NLTX treatment significantly and independently increased ARC NPY mRNA and decreased UCP mRNA levels in brown fat, suggesting a complex interaction between hypothalamic NPY and endogenous opioids in the regulation of energy balance.

Palatability-induced hyperphagia increases hypothalamic Dynorphin peptide and mRNA levels.

Opioid involvement in regulating the intake of highly palatable diets was studied by examining the effect of feeding either a cornstarch-based diet (CHO) or a high fat diet containing sucrose (Fat/Sucrose) on hypothalamic opioid levels. Rats received either CHO ad libitum, Fat/Sucrose ad libitum, Fat/Sucrose pair-fed to the caloric intake of CHO, or Fat/Sucrose at 60% of ad libitum Fat/Sucrose intake. Animals receiving Fat/Sucrose ad libitum consumed more calories and gained more weight than animals receiving CHO (P < 0.001). Relative to CHO, ad libitum intake of Fat/Sucrose elevated proDynorphin mRNA levels in the arcuate and Dynorphin A1-17 levels in the paraventricular nucleus (PVN) (P < 0.05), but did not affect arcuate mRNA levels of proEnkephalin or proOpiomelanocortin (POMC), or PVN levels of Met-Enkephalin or beta-Endorphin. Pair-feeding the Fat/Sucrose diet to the level of intake of the CHO diet resulted in levels of proDynorphin and Dynorphin A1-17 that were similar in the two diet groups. Pair-feeding Fat/Sucrose reduced mRNA levels of proDynorpin, proEnkephalin and POMC, and Dynorphin A1-17 levels, relative to ad libitum feeding of Fat/Sucrose. Met-Enkephalin and beta-Endorphin were not affected by dietary treatment. Feeding Fat/Sucrose at 60% of ad libitum intake resulted in mRNA levels of proDynorphin, proEnkephalin and POMC, and Dynorphin A1-17 levels that were similar to those observed in CHO group. Hypothalamic Dynorphin A1-17 and proDynorphin mRNA levels are stimulated by feeding a highly palatable diet rich in fat and sucrose. The increased synthesis may be due in part to a palatability-induced overconsumption of calories. Caloric restriction of the same diet decreases mRNA levels of proDynorphin, proEnkephalin and POMC, as well as levels of Dynorphin A1-17.

Chronic food restriction and acute food deprivation decrease mRNA levels of opioid peptides in arcuate nucleus.

Although opioid administration induces food intake, the relationship between endogenous opioid synthesis and food consumption is unclear. Two studies examined the effects of food restriction and deprivation on opioid mRNA levels in the arcuate nucleus (ARC) of the rat. Body weight significantly decreased following food restriction and deprivation (P < 0.0001). In experiment 1, food restriction of 10,20,30, and 40% (g) of ad libitum intake for 14 days decreased proDynorphin (proDyn), proEnkephalin (proEnk), and proOpiomelanocortin (POMC) mRNA levels in a linear fashion relative to changes in body weight (r = 0.398, P = 0.0011; r = 0.455, P = 0.0028; r = 0.292, P = 0.0642, respectively). In experiment 2, 48 h deprivation significantly decreased mRNA levels of proDyn and POMC by 23.7% (P < 0.05) and 45.6% (P < 0.01), respectively, whereas 24 h food deprivation decreased POMC mRNA by 43.% (P < 0.01). proEnk mRNA was not affected by 24- or 48-h food deprivation. Restricting food intake suppressed mRNA levels of proDyn, proEnk, and POMC by 29.7, 22.3, and 44.4%, respectively, in 20% restricted rats and by 35.5, 26.8, and 45.6%, respectively, in 40%restricted rats (P < 0.01). It appears that ARC mRNA levels of proDyn, proEnk, and POMC are directly related to the amount of food consumed and/or changes in body weight in food-restricted and food-deprived rats.