Biomedical subjects

C J Billington

Publications and source records attributed to C J Billington.

At least 37 records · Page 2Linked to original sources

PubMed2000

Opioids affect acquisition of LiCl-induced conditioned taste aversion: involvement of OT and VP systems.

Aversive properties of lithium chloride (LiCl) are mediated via pathways comprising neurons of the nucleus of the solitary tract (NTS) and oxytocin (OT) and vasopressin (VP) cells in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Because opioids act on brain regions that mediate effects of LiCl, we evaluated whether administration of opioids shortly before LiCl in rats influences 1) development of conditioned taste aversion (CTA) and 2) activation of NTS neurons and OT/VP cells. Neuronal activation was assessed by applying c-Fos immunohistochemical staining. Three opioids were used: morphine (MOR), a mu-agonist, butorphanol tartrate (BT), a mixed mu/kappa-agonist, and nociceptin/orphanin FQ (N/OFQ), which binds to an ORL1 receptor. BT and N/OFQ completely blocked acquisition of CTA. MOR alleviated but did not eliminate the aversive effects. Each of the opioids decreased LiCl-induced activation of NTS neurons as well as OT and VP cells in the PVN and SON. We conclude that opioids antagonize aversive properties of LiCl, presumably by suppressing activation of pathways that encompass OT and VP cells and NTS neurons.

Analgesics, Opioid↗

PubMed1999

Discriminative stimulus effects of morphine: central versus peripheral training.

While it is well known that rats can discriminate a peripheral injection of morphine from a saline injection, to our knowledge no one has trained rats to discriminate a direct brain-site injection of morphine from saline. In the present series of studies, one group of rats was trained to discriminate morphine (0.3 microgram) from saline injected into the perifornical area of the hypothalamus (PFA), a process that took rats about 37 sessions to learn. A dose response generalization curve for PFA-injected morphine (0.01, 0.03, 0.1, and 0.17 microgram) was generated in which the two highest doses of morphine generalized to the morphine-appropriate training stimulus. Intraperitoneal (i.p.) injection of 3 mg/kg, but not 1 mg/kg morphine, resulted in morphine-appropriate responding in the PFA morphine-trained rats. A second group of rats was trained to discriminate i.p. injections of 3 mg/kg morphine from injections of saline. A dose-response generalization test for i.p.-injected morphine (0.3, 0.56, 1.0, and 1.7 mg/kg) was conducted in which the 0.17 mg/kg dose of morphine generalized to the morphine-appropriate training stimulus. Generalization tests using PFA-injected morphine doses (0.17, 0.56, 1.0, and 3.0 microgram) failed to result in morphine-appropriate responding in the i.p. morphine-trained rats. Naloxone administered into the PFA (50 microgram) or the periphery (3 mg/kg, i.p.) blocked morphine discrimination in the PFA-trained rats. However, when naloxone was injected into the PFA (50 microgram) together with i.p. morphine (3 mg/kg) in animals trained using i.p. injections, the antagonist failed to block morphine-appropriate responding. Thus, while peripheral injection of morphine generalized to the discriminative stimulus effects of morphine produced under PFA-injection training, the opposite effects were not noted.

Analgesics, Opioid↗

PubMed1999

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.

Animal Feed↗

PubMed1999

Feeding response to central orexins.

Orexin A and orexin B were microinjected into the perifornical hypothalamus (PFH), lateral hypothalamus (LH), hypothalamic paraventricular nucleus (PVN), and ventral tegmental area (VTA) of male Sprague-Dawley rats. Orexin B (15 nmol) was also injected into the lateral cerebral ventricle (i.c.v.). Orexin A (>/=500 pmol) stimulated feeding in the PFH and LH, but not in the VTA or PVN. Orexin B stimulated feeding only when injected i.c.v.

Animals↗

PubMed1999

The effect of naltrexone on taste detection and recognition threshold.

Eighteen healthy female volunteers were administered 50 mg naltrexone in a double-blind, placebo control study. Relative taste detection and recognition thresholds for sweet, salty, sour and bitter taste and liking for and perception of sucrose solutions were determined at baseline and 1 hour after administration of naltrexone. Naltrexone did not alter relative taste detection and recognition thresholds for any of the four tastes or perception of sweetness. However, a significant, but slight, decrease in liking for sucrose solutions occurred after naltrexone administration. These findings suggest that opioid-dependent intake is independent of changes in taste perception in humans.

Adult↗

PubMed1999

The effect of naloxone on food-motivated behavior in the obese Zucker rat.

We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule 3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses required for a reinforcer eventually exceeded its value, termed the "break point", a sensitive measure of food motivated behavior. Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P = 0.01) but not for sweet pellets (51.6 versus 38.5, P = 0.31). We determined if naloxone (0.01-3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free access to food than in rats working for food.

Animals↗

PubMed1999

Binding of GM-CSF to adherent neutrophils activates phospholipase D.

When the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor was incubated with neutrophils adherent to plastic tissue culture plates or plates coated with extracellular matrix proteins, a rapid (3 min) but transient formation of phosphatidic acid was observed. This stimulation was dependent on the dose of GM-CSF, with an EC50 of 140 pM, and was further enhanced (up to 350%) with the PA phosphatase inhibitor propranolol in a dose-dependent manner. Conversely, GM-CSF was unable to trigger any PA formation in neutrophils maintained in suspension, even in the presence of soluble fibronectin. However, GM-CSF did prime the cells for enhanced PA formation in the presence of a secondary stimulus (fMet-Leu-Phe or PAF). GM-CSF also caused a time-dependent stimulation of diacylglycerol formation in adherent, but not suspended, cells and elicited a time-dependent stimulation of phosphatidylethanol formation, with a concomitant decrease in the formation of PA only at early (< 7 min) times. These observations were consistent with a rapid activation of the enzyme phospholipase D in adherent cells stimulated with GM-CSF. Additional data indicated that the source of DAG was PLD coexisting with PLC, especially at later times ( > 7 min) of stimulation with GM-CSF. Finally, the formation of PA and PEt, and to a minor extent, DAG, were inhibited by the protein tyrosine kinase inhibitor erbstatin in conditions in which tyrosine phosphorylation occurred. Taken together the data indicate that GM-CSF rapidly activates PLD in adherent cells, which is responsible for the generation of PA. Thus, PLD activation is an early event in neutrophil signal transduction following exposure of adherent cells to GM-CSF.

Adrenergic beta-Antagonists↗

PubMed1999

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.

Animals↗

PubMed1999

Thyroid function and energy intake during weight gain following treatment of hyperthyroidism.

OBJECTIVE: Individuals with hyperthyroidism lose weight despite increased appetite and food intake, and weight is regained after treatment of hyperthyroidism. We asked whether this weight regain is purely a function of lowered metabolic rate coincident with lowered thyroid hormone concentrations or if the weight gain is related to food-energy overconsumption. METHODS: Ten unselected patients with hyperthyroidism treated with 131I were studied. The following measurements were made at 0, 1, 2, 3, 6, and 12 months: total food energy, carbohydrate, fat and protein consumption; serum thyroxine (T4); serum triiodothyronine (T3); T3 resin uptake; serum thyroid stimulating hormone (TSH); weight; height; and 24-hour urinary urea excretion. RESULTS: Inverse changes in body weight and food energy consumption/kg throughout the period of observation was a striking finding (mean initial weight 67.1+/-5 kg, final weight 76.4 kg+/-3 kg, premorbid weight 77.1+/-5 kg). The initial and final food energy intake was 3005+/-199 and 2597+/-137 Kcal/24 hrs, respectively. The thyroid hormone concentrations declined inversely relative to weight gain during the first months of the study, but later the thyroid hormones increased while weight gain continued. Initial serum T4 15.0+/-1 value at three months was 4.0+/-1.0 mg/dl, final T4 11.0+/-1. CONCLUSION: We conclude that weight gain following treatment of hyperthyroidism is due to 1) reduction in metabolic rate consequent upon the decreased thyroid hormone concentrations and 2) food energy intake which was initially greater than required to maintain individuals' premorbid weight. As body weight increased, food intake declined and both reached an asymptotic limit.

Adult↗

PubMed1999

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.

Animals↗

PubMed1999

Role of lipid type on morphine-stimulated diet selection in rats.

Administration of morphine is said to increase fat consumption among rats allowed to self-select nutrients. However, fats represent a diverse group of molecules, differing in metabolic and sensory properties. Despite this, lipid has yet to be manipulated as a variable in drug-stimulated nutrient selection studies. To determine whether lipid source can impact daily and morphine-stimulated (1, 3, and 10 mg/kg) diet intake, rats were provided with a choice between a high-fat and high-carbohydrate diet in three regimens in which the source of fat was varied between vegetable shortening, lard, or corn oil. Daily and morphine-stimulated diet selections were determined under all conditions. Under daily feeding conditions, rats ate more of the high-lipid diet compared with the high-carbohydrate diet when vegetable shortening or lard was the main lipid alternative, but lipid and carbohydrate intake did not differ when corn oil was the main lipid alternative. When rats were stimulated with morphine, the percentage of lipid increased relative to baseline intake only when the lipid diets were the preferred alternatives (i.e., vegetable shortening or lard). When preference between lipid and carbohydrate diets was neutral (i.e., corn oil condition), morphine did not enhance lipid consumption. These results indicate that morphine increases consumption of total energy or preferred diets and not lipid per se.

Animals↗

PubMed1999

Obesity and aging.

This review focuses on studies that pertain to obesity and aging. The prevalence of obesity in the elderly is discussed, with an emphasis on body-fat distribution as it relates to morbidity and mortality rates. Treatment options, such as physical activity, growth hormones, and drug therapy, are briefly mentioned. A section that covers some of the most recent issues pertaining to the neuroregulation of feeding and energy expenditure is included. Finally, we briefly discuss anorexia in the aged.

Adult↗

PubMed1998

An aggrecan-degrading activity associated with chondrocyte membranes.

The breakdown of aggrecan in cartilage is, in part, mediated by an enzyme named aggrecanase that cleaves within the interglobular domain of the molecule between a glutamic residue and an alanine residue. Although the enzyme cleavage site has been identified, the identity, characteristics and localization of this enzyme remain unclear. We have demonstrated that membranes isolated from stimulated chondrocytes are able to generate aggrecan fragments that are labelled by an antibody that recognizes the new N-terminus formed by aggrecanase activity. It was further shown that the membrane activity was a metalloproteinase but was not inhibited by the naturally occurring matrix metalloproteinase (MMP) inhibitors, TIMPs 1 and 2. These results show that an aggrecanase activity is associated with the membranes of the chondrocytes and is a metalloproteinase, but might not be a member of the MMP family.

Aggrecans↗

PubMed1998

Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands.

It has been reported that intraventricular administration of the melanocortin 4 receptor (MC4-R) agonist MT II and antagonist SHU9119 alter food intake. We found that MT II and SHU9119 have extremely potent effects on feeding when injected in the paraventricular nucleus (PVN), a site where MC4-R gene expression is very high. Our finding provides direct evidence that MC4-R signaling is important in mediating food intake and that melanocortin neurons in the PVN exert a tonic inhibition of feeding behavior. Chronic disruption of this inhibitory signal is a possible explanation of the agouti-obesity syndrome.

Animals↗

PubMed1998

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.

Animals↗

PubMed1998

Association between the amygdala and nucleus of the solitary tract in mu-opioid induced feeding in the rat.

The central nucleus of the amygdala (CNA) and the nucleus of the solitary tract (NTS) are important in the regulation of ingestive behavior. We evaluated whether opioid-opioid signaling between the CNA and rostral NTS (rNTS) affect feeding behavior. To test this, rats were doubly cannulated with one cannula placed in the rNTS and one cannula in the CNA, allowing for co-administration of an opioid agonist into one site and an opioid antagonist into the other. Tyr-D-Ala-Gly-(me) Phe-Gly-ol (DAMGO) (2 nmol) injected into the CNA (CNA DAMGO) increased feeding more than two-fold compared to the vehicle-injected rats. This increase in food intake was blocked when doses of 26.5 and 79 nmol of naltrexone (NTX) were injected into the rNTs. In the reverse situation, rNTS DAMGO increased food intake above control levels, and CNA NTX blocked DAMGO-induced feeding when administrated in doses of 26.5 and 79 nmol. This suggests that a bi-directional opioid-opioid signaling pathway exists between the CNA and the rNTS which influences feeding via mu-opioid receptors.

Amygdala↗

PubMed1998

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.

Animals↗

PubMed1998

Obesity: progress through genetic manipulation.

Transgenic mice have been produced that either lack or overproduce neuroregulatory substances implicated in the control of food intake and body weight. Are such mice useful models for understanding the underlying etiology of obesity in humans?

Animals↗