naloxone and Obesity

In this large population-based cohort, individuals with more-severe obesity, central obesity, or genetic predisposition for obesity are at higher risk of developing severe-COVID-19.. The use of different references for the classification of a high %BF implied a difference in the diagnostic sensitivity of the BMI. Higher cutoff points resulted in greater sensitivity and ability to differentiate individuals with and without obesity.

Topics: Acyclic Monoterpenes; Adipose Tissue; Adolescent; Adult; Aged; Aged, 80 and over; Air Pollutants; Air Pollutants, Occupational; Amino Acid Transport Systems; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Arthrobacter; Bacteria; Bacteriological Techniques; Benzaldehydes; Biodegradation, Environmental; Biofilms; Biological Transport; Biomarkers; Biomass; Bioreactors; Body Composition; Body Mass Index; Brassica; Brazil; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Caco-2 Cells; Cadmium; Calcium; Calcium Carbonate; Calcium Channels; Catalysis; Cell Degranulation; Cell Line; Cell Membrane; Chitosan; Chromatography, High Pressure Liquid; Chromium; Cobalt; Cohort Studies; Colony Count, Microbial; Composting; Copper; COVID-19; Cross-Sectional Studies; Cytoplasm; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diarrhea; Diethylhexyl Phthalate; Dose-Response Relationship, Drug; Drug Implants; Drug Stability; Drug Synergism; Electroplating; Endometrial Neoplasms; Endometrium; Environmental Monitoring; Environmental Restoration and Remediation; Estradiol; Estrogens; Feces; Female; Food Microbiology; Food Preservation; Fruit and Vegetable Juices; Gasotransmitters; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Glutathione; Gold; Graphite; Growth Hormone; Harm Reduction; Hot Temperature; Humans; Hydrocortisone; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydrogen-Ion Concentration; Ileum; Imidazoles; Injections, Intraperitoneal; Insecticides; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Intestinal Absorption; Light; Lignin; Liver; Magnetics; Male; Manganese; Mast Cells; Melanoma; Membrane Potentials; Metals; Methadone; Microbial Viability; Microplastics; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Middle Aged; Mitochondrial Swelling; Molecular Dynamics Simulation; Monophenol Monooxygenase; Morocco; Naloxone; Naltrexone; Nanocomposites; Nanomedicine; Nanoparticles; Narcotic Antagonists; Neonicotinoids; Nitric Oxide; Nitro Compounds; Nitrogen; Nitrogen Compounds; Obesity; Obesity, Abdominal; Occupational Exposure; Ontario; Opiate Substitution Treatment; Opioid-Related Disorders; Oryza; Overweight; Oxidative Stress; Oxides; Oxygen; Perception; Photoelectron Spectroscopy; Plants; Plastics; Point Mutation; Polychlorinated Biphenyls; Polycyclic Aromatic Hydrocarbons; Potassium; Premenopause; Prodrugs; Prospective Studies; Protons; Pyrolysis; Qualitative Research; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resins, Synthetic; Rhodamines; Risk Factors; ROC Curve; Salmo salar; SARS-CoV-2; Seawater; Severity of Illness Index; Sewage; Social Media; Soil; Soil Microbiology; Soil Pollutants; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Staining and Labeling; Stainless Steel; Steel; Stress, Physiological; Substance Abuse Treatment Centers; Symporters; T-Lymphocytes; Toluene; Triclosan; Ultraviolet Rays; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Purification; Welding; X-Ray Diffraction; Young Adult

Psychopharmacologic treatment is playing a greater role in the management of patients with eating disorders. In this paper, we review randomized, placebo-controlled trials (RCTs) conducted in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other eating disorders over the past 3 years. Fluoxetine remains the only medication approved for an eating disorder, that being BN. RCTs of antipsychotics in AN have had mixed results; the only agent with some evidence of efficacy is olanzapine. One study suggests dronabinol may induce weight gain in AN. Preliminary studies suggest lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED. In BED with obesity or overweight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation. Also in BED, three RCTs suggest the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggests intranasal naloxone may decrease time spent binge eating. There remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions.

Topics: Administration, Intranasal; Anorexia Nervosa; Anti-Obesity Agents; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Baclofen; Binge-Eating Disorder; Bulimia Nervosa; Bupropion; Central Nervous System Stimulants; Chromium Compounds; Humans; Lisdexamfetamine Dimesylate; Morphinans; Naloxone; Narcotic Antagonists; Obesity; Randomized Controlled Trials as Topic

Beta-endorphin were detected in the endocrine pancreas and seem able to influence insulin and glucagon release. Hence, endogenous opioids could have a role in glucoregulation and in the pathogenesis of obesity beyond the previously detected effects on appetite. Metabolic abnormalities, such as hyperinsulinemia, insulin-resistance and obesity, are common features of polycystic ovary syndrome (PCOS), and seem to have a pathogenetic role in this disorder. A link between opioids and PCOS-related hyperinsulinism is suggested by the finding of altered central opioid tone and elevated beta-endorphins levels, directly correlated with body weight, in these patients. Furthermore, naloxone and naltrexone significantly reduce the insulin response to glucose load only in hyperinsulinemic PCOS patients. This effect is obtained chiefly through an improvement of insulin clearance. Naltrexone is also able to ameliorate the abnormal gonadotrophins secretion and to improve the ovarian responsiveness in obese PCOS women undergoing ovulation induction with exogenous GnRH. Such effects are believed to be obtained through an amelioration of hyperinsulinemia. Gonadal steroids modulate the opioid system both centrally and in peripheral districts. Nevertheless, the decline of ovarian function does not abolish the opioidergic control of glucoregulation. Post-menopausal period is characterised by a high prevalence of hyperinsulinemia and insulin-resistance. In particular, an association between hyperinsulinemia and increased opioid activity was found in postmenopausal women showing a central body fat distribution. Both naloxone and naltrexone ameliorate the metabolic imbalance also when it appears in the climacteric period, and mainly by increasing insulin clearance. The benefits of naltrexone may represent in the future a useful tool for the treatment of women with hyperinsulinism in the clinical practice.

Topics: Clinical Trials as Topic; Endorphins; Female; Humans; Hyperinsulinism; Insulin Resistance; Menopause; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Polycystic Ovary Syndrome

Topics: Amino Acid Sequence; Animals; Appetite Regulation; beta-Endorphin; Endorphins; Humans; Models, Biological; Molecular Sequence Data; Naloxone; Obesity; Receptors, Opioid; Stress, Psychological

Animal studies have demonstrated a robust role for the endogenous opioid system in the control of food intake. In humans, selective opioid antagonists such as naloxone, naltrexone, and nalmefene have been shown in some studies to reduce total food intake by up to 30% and to alter food preferences in short-term experimental trials in normal-weight subjects, as well as in obese and bulimic patients. The value of naloxone and naltrexone in the long-term treatment of eating disordered patients, however, must be considered very limited. The published treatment studies do not justify the routine use of naloxone and naltrexone in patients with Prader-Willi syndrome, obesity, bulimia nervosa, or anorexia nervosa because of their unprofitable risk/benefit ratios, although further work, particularly focused on some of the newer antagonists, should be undertaken.

Topics: Appetite Depressants; Dose-Response Relationship, Drug; Eating; Feeding and Eating Disorders; Feeding Behavior; Female; Humans; Male; Naloxone; Naltrexone; Narcotic Antagonists; Obesity

Since increased opiate production in obesity has been reported, the effects of naloxone in obese subjects were studied in order to ascertain whether endogenous opioid peptides play a role in the abundant insulin secretion of obesity. The results obtained showed that intravenous administration of naloxone considerably reduced insulin of obese subjects to a mixed meal, whereas it did not modify the blood insulin response to arginine or glucose infusion. Glucagon secretion to ingestion of a mixed meal and to arginine infusion was not modified by the opioid receptor blocking agent. This study seems to indicate that hyperproduction of endogenous opioid peptides in obesity increases insulin secretion stimulated by food intake, whereas it does not appreciably affect insulin production stimulated by circulating glucose or aminoacids.

Topics: Adolescent; Adult; beta-Endorphin; Endorphins; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Naloxone; Obesity

Considerable work across the last 10 yr has implicated the endogenous opioid peptides in the regulation of ingestion. The opioid antagonists, such as naloxone and naltrexone, reduce intake of water, flavored water, and food. Naloxone's effects are pharmacologically specific, ie, its effects are dose-related and stereoselective. Further, a variety of antagonists produce similar effects. A primary site of action of naloxone, with respect to intake, is in the central nervous system. Naloxone's effects are also behaviorally specific, ie, its effects seem particularly related to palatability functions. The effects of opioid agonists, in small doses, enhance intake of some nutrients, but these effects are not opposite those of the antagonists. Benzodiazepines enhance drinking and eating and apparently interact with opioid systems. These observations combine with those directly measuring features of the endogenous opioid peptides to support a conclusion that opioid peptides are part of a system for regulating ingestion.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Brain; Drinking Behavior; Endorphins; Feeding Behavior; Humans; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Obesity; Receptors, Opioid

Guidelines for the medical therapy of obstructive sleep apnea are difficult to define precisely. While some elegant investigations have been completed, most study populations have been small. Also, the long-term effects of most forms of therapy are not known. Some patients will respond to a given form of therapy or combination of therapies while others will not. In most instances the responders cannot be recognized prior to the institution of therapy and a cycle of trial and error ensues. One of the best nonsurgical approaches appears to be weight loss, albeit unsuccessful in most cases. Almost all experts would agree, however, that in nonemergent situations weight loss should be strongly suggested. Nasal CPAP appears to be the single most promising device. Protriptyline may have a role, although in our opinion its true efficacy remains to be determined. Oxygen will probably serve more an adjunctive role in therapy, and medroxyprogesterone appears to be beneficial only in the treatment of the obesity-hypoventilation syndrome. A reasonable approach to the medical treatment of the obstructive sleep apnea patient should include, first, by history, physical examination, and appropriate laboratory testing, elimination of anatomically correctable, pharmacologic, or endocrinologic causes of OSA. If apnea length, degree of desaturation, cardiac arrhythmias, or levels of hypersomnolence are so severe as to be potentially life threatening, immediate tracheostomy is suggested. In specialized centers, nasal CPAP would be used. In less severely affected patients, medical management, as discussed above, should begin. We believe that in view of the lack of controlled trials demonstrating which form of therapy is best, the clinician must recommend therapy on the basis of local clinical experience and patient acceptance. Of fundamental importance is the need for serial reevaluation so that the impact of therapeutic failure can be minimized.

Topics: Almitrine; Central Nervous System Stimulants; Diet, Reducing; Humans; Intubation; Male; Naloxone; Nasopharynx; Obesity; Oxygen Inhalation Therapy; Piperazines; Positive-Pressure Respiration; Progesterone; Protriptyline; Sleep Apnea Syndromes; Theophylline

There is evidence that endogenous opiates are involved in the control of feeding in experimental animals. Several types of experimental obesity are associated with increased opiate production and/or increased numbers and sensitivity of opiate receptors. Research with experimental animals suggests that nutrients, particularly sugar, have an effect on feeding behavior that is mediated by opiates. For instance, the obesity-producing effect of a palatable diet in rodents is blocked by opiate antagonists. Stress induced feeding in rodents leads to preferential sucrose ingestion and is blocked by opiate antagonists and beta-endorphin. The effect of nutrients on the endogenous opiate system of humans is less clear. Clinical experience suggest that carbohydrates (sugar in particular) play a role in binge eating and obesity. Many binge eaters preferentially eat sweets during a binge. Many obese individuals consume more than half of their total daily calories as carbohydrates. Sweet snacking is a frequent behavior at times of stress. Recent evidence suggests that sugar can lead to increased beta-endorphin production in obese subjects.

Topics: Animals; beta-Endorphin; Diet; Endorphins; Feeding and Eating Disorders; Feeding Behavior; Glucose; Humans; Hyperphagia; Male; Naloxone; Narcotics; Obesity; Time Factors

Topics: Animals; Appetite; Brain; Chemical Phenomena; Chemistry; Digestive System; Endorphins; Guinea Pigs; Humans; Hunger; Hypothalamus; Mice; Morphine; Naloxone; Obesity; Personality; Pituitary Gland, Anterior; Rats; Receptors, Opioid; Stress, Psychological

Topics: Adrenal Glands; Animals; Body Weight; Central Nervous System; Diet; Digestive System Physiological Phenomena; Eating; Energy Intake; Energy Metabolism; Feeding Behavior; Humans; Hyperphagia; Hypothalamus; Models, Biological; Morphine; Naloxone; Obesity; Satiety Response

To evaluate the influence of the opioid system on the hypothalamic-pituitary-adrenal axis in women with polycystic ovary syndrome (PCOS).. Controlled clinical study.. Academic research environment.. Eight lean and 12 obese women with PCOS, and seven lean and 5 obese control subjects.. Each patient received an i.v. bolus of naloxone at a dose of 125 microgram per kilogram of body weight; 48 hours later, each patient received 16 mg of loperamide p.o.. Samples were collected for 2 hours for the naloxone test and for 3 hours for the loperamide test. Levels of adrenocorticotropic hormone (ACTH) and cortisol were measured in all plasma samples.. The obese women with PCOS had a greater ACTH and cortisol response to opiate blockade than either the lean women with PCOS or the control subjects, but there was no difference between the lean or obese control subjects and the lean women with PCOS. There was no difference in the responsiveness of the hypothalamic-pituitary-adrenal axis to loperamide between the PCOS and control groups.. The data indicate that the sensitivity of the hypothalamic-pituitary-adrenal axis to opioids cannot be altered in women with PCOS. However, abnormalities of the hypothalamic-pituitary-adrenal axis in women with PCOS could be central in origin, as suggested by the effects of naloxone administration, and probably are related to the anthropometric characteristics of these hyperandrogenic patients.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Body Weight; Female; Humans; Hydrocortisone; Hypothalamus; Loperamide; Naloxone; Narcotic Antagonists; Narcotics; Obesity; Pituitary Gland; Polycystic Ovary Syndrome

To evaluate the influence of body mass on the hypothalamic-pituitary-adrenal (HPA)-axis response to naloxone in polycystic ovary syndrome (PCOS).. Controlled clinical study.. Academic research environment.. Ten lean and 10 obese women with PCOS compared with 7 lean and 8 obese control subjects matched for body mass index.. Each patient received an IV bolus of naloxone at a dosage of 125 microg/kg.. Samples were collected 30 minutes before and 0, 15, 30, 60, 90, and 120 minutes after injection: ACTH and cortisol levels were measured in all plasma samples.. No significant differences were found in the ACTH and cortisol responses to opioid blockade between lean women with PCOS and lean as well as obese control subjects; conversely, obese patients with PCOS showed a higher ACTH and cortisol responses to naloxone compared with all other groups.. Hypothalamic-pituitary-adrenal-axis abnormalities of PCOS may be central in origin and abdominal obesity seems to play a key role in the HPA-axis hyperactivity of women with PCOS when naloxone is administered.

Topics: Adrenocorticotropic Hormone; Adult; Body Mass Index; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Naloxone; Narcotic Antagonists; Obesity; Pituitary-Adrenal System; Polycystic Ovary Syndrome

Hyperactivity of the HPA axis is a possible mechanism underlying abdominal obesity. We aimed to evaluate in premenopausal women with abdominal obesity, (i) the hypothalamic-pituitary-adrenal (HPA) axis responses to direct pituitary stimulation with corticotrophin releasing hormone (CRH) and to opioid blockade with naloxone, and (ii) the interaction between short-term serotoninergic activation with dexfenfluramine (dF), a serotonin-release agonist, and these responses.. Eight obese women (mean BMI, 35 kg/m2) with waist to hip ratio (WHR) > 0.85 were tested with CRH (1 microgram/kg i.v.) and naloxone (125 micrograms/kg i.v.) before and at the end of two treatment periods with dF (15 mg twice daily for 7 days) and placebo (washout 7 days) in a cross-over design. Eight normal weight control women were tested with CRH and naloxone.. Prior to treatment, ACTH and cortisol responses to naloxone (areas under the curve) were significantly higher in obese women then in control women (P = 0.027 and P = 0.035 respectively) dF treatment resulted in significant (P < 0.05) reduction of ACTH and cortisol increments. In contrast, ACTH and cortisol responses to CRH were not significantly different in obese and control subjects and were unaffected by dF treatment.. We conclude that women with abdominal obesity have hyperreactivity of the HPA axis to opiod blockage and that dexfenfluramine treatment reduces this hyperactivity.

Topics: Adrenocorticotropic Hormone; Adult; Body Constitution; Body Mass Index; Corticotropin-Releasing Hormone; Cross-Over Studies; Female; Fenfluramine; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Naloxone; Narcotic Antagonists; Obesity; Pituitary-Adrenal System; Serotonin Agents

To test the hypothesis that endogenous opiate peptides selectively influence hedonic response to sweet and high-fat foods, the opiate antagonist naloxone, opiate agonist butorphanol, and a saline placebo were administered by intravenous infusion to 16 obese and 25 normal-weight women. Twenty of the women (10 obese, 10 lean) fulfilled DSM-III-R diagnostic criteria for bulimia nervosa, as determined by psychiatric interview. During drug infusion the women tasted and rated 20 sweetened dairy products and were presented with eight snack foods of varying sugar and fat content. Naloxone suppressed hedonic responses in all subject groups and suppressed the consumption of sweet and high-fat foods in binge eaters, but not in nonbingers. Food intakes of obese women were not affected by naloxone. Butorphanol had no effect on either hedonic response or on food consumption in any group. Although opiate blockade is not a viable strategy for weight reduction in the treatment of obesity, it may be useful in the clinical management of the binge-eating disorder.

Topics: Adult; Bulimia; Butorphanol; Dietary Carbohydrates; Dietary Fats; Double-Blind Method; Eating; Energy Intake; Female; Food Preferences; Humans; Infusions, Intravenous; Naloxone; Obesity; Taste

An overactive endogenous opioid peptide system (EOP) in the hypothalamus of the obese rats could contribute to a subnormal metabolic response to cold stress. Specific mu, delta, kappa opioid receptor antagonists and naloxone were infused into cannulaes aimed at the paraventricular nucleus (PVN) of awake freely moving obese (LA/N-cp corpulent) and lean littermate rats. Metabolic responses were measured by indirect calorimetry during thermoneutrality (30 degrees C) and at 10 degrees C for 60 minutes each. When expressed relative to metabolic body size (kg(-.75)) obese rats had lower values (obese = 21.1 +/- 1.9 vs. lean = 27.9 +/- 2.7 ml x kg(-.75) x min, mean +/- s.d., p < 0.05) at 10 degrees C during saline infusion. EOP antagonist infusions at 30 degrees C had no effect on metabolic rate for either lean or obese animals. Mu (23.5 +/- 3.4 ml x kg x (-75) x min) and delta (23.0 +/- 2.0) antagonism and naloxone (25.0 +/- 2.3) significantly increased the metabolic response to cold in obese but not lean rats. These data suggest that certain subtypes of EOP receptors in or near PVN are overactive in obese rats. This overactive state may inappropriately inhibit the thermogenic response to cold stress in obesity.

Topics: Animals; Cold Temperature; Enkephalin, Leucine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Opioid Peptides; Oxygen Consumption; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Stress, Physiological; Thermogenesis

In this study, we investigated the hypothesis that increased opioid activity may be involved in the development of hyperinsulinemia in women with obesity and abdominal body fat distribution. Two groups of nine obese body (body mass index [BMI], 30 to 40 kg/m2) women with abdominal (A-ob) (waist to hip ratio [WHR] greater than 0.85) or gluteo-femoral (F-ob) (WHR greater than or equal to 0.80) fat distribution were examined and compared with eight normal-weight controls. Basal beta-endorphin levels were higher in the A-ob group than in the other groups. Each woman underwent two oral glucose tolerance tests (OGTT, 75 g glucose). A bolus of naloxone (0.8 mg) followed by a constant infusion of naloxone (0.04 mg/kg/h) or saline was also administered during the glucose challenge in random order, and blood samples for glucose, insulin, and C-peptide were collected at regular times after glucose administration. No difference was observed in basal or stimulated glucose concentrations between the three groups, nor between the saline or naloxone study. However, basal and stimulated insulin levels were significantly higher in obese women (particularly in the A-ob group) than in controls. Naloxone administration, however, did not significantly modify insulin and C-peptide glucose-stimulated concentrations in controls and in the F-ob group, whereas it significantly reduced (by approximately 47%) insulin levels in the A-ob group. Partial correlation coefficients showed a significant negative correlation between percent variation of glucose-stimulated insulin incremental areas during the naloxone study and the WHR in all women considered together (r = .544, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abdomen; Adipose Tissue; Adult; beta-Endorphin; C-Peptide; Endorphins; Female; Humans; Insulin; Naloxone; Obesity

To evaluate whether the supposed physiological interaction between serotoninergic and opioidergic pathways in the modulation of PRL release is preserved in human obesity, a pathological condition in which these two systems are greatly impaired.. According to a single-blind randomized procedure, three tests were performed: test A (oral placebo + saline infusion over 5 hours), test B (fenfluramine, a well known serotoninergic drug, 60 mg orally + saline infusion over 5 hours) and test C (fenfluramine at the same dose + naloxone, an opiate receptor antagonist, infusion over 5 hours at a dose of 3 mg/h).. Ten obese women (body mass index 34.4 +/- 2.3 kg/m2, mean +/- SE) and ten normal-weight sex and age-matched subjects (body mass index 22.3 +/- 2.4 kg/m2) volunteered for the study.. At each test, blood samples for PRL determination were collected in basal conditions (time 0) and every hour for 5 hours. Plasma PRL was determined by radioimmunoassay.. In controls, naloxone significantly reduced the clear-cut PRL increase induced by fenfluramine. In obese patients, serotoninergic stimulation caused an increment in PRL levels similar to that in the controls, but opioid receptor blockade by naloxone did not affect this response.. These findings confirm that there is a physiological relationship between the serotoninergic and the opioidergic systems in the control of PRL secretion and show that this interaction is not present in obese subjects. Our data provide indirect proof of the functional impairment of these two systems in human obesity.

Topics: Adolescent; Adult; Female; Fenfluramine; Humans; Hypothalamus; Naloxone; Obesity; Prolactin; Single-Blind Method

Orocecal transit time was assessed with lactulose hydrogen breath test in 12 obese patients during intravenous infusion of placebo or naloxone 40 micrograms/kg/hr given in randomized order and in double-blind conditions. Transit time was also evaluated in 22 healthy controls. Orocecal transit was significantly (P less than 0.01) longer in the obese patients, during placebo treatment (median 130, range 100-200 min) than in the healthy controls (median 75, range 40-170 min). Compared with placebo, transit time in the obese subjects was delayed (P less than 0.05) during naloxone treatment (median 150, range 100-230 min).

Topics: Adult; Breath Tests; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Naloxone; Obesity; Random Allocation

Topics: Adult; Brain; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Eating; Energy Intake; Female; Humans; Hydrocortisone; Infusions, Intravenous; Male; Naloxone; Obesity; Receptors, Opioid

Opiates stimulate the growth hormone and prolactin responses to stimuli in non-obese humans. Obese patients, however, show lowered growth hormone and prolactin responses and raised beta-endorphin levels. We therefore investigated the effect of the opiate antagonist naloxone on the stimulated growth hormone and prolactin secretions in a controlled double-blind study in obese patients. All patients received 200 micrograms TRH and 0.5 g/kg b.w. arginine together with 2 mg of naloxone or placebo i.v. in a randomized sequence. The TRH- and arginine-induced increases in prolactin and growth hormone were significantly greater after administration of naloxone (p less than 0.05). Naloxone also produced a significant increase in ACTH, cortisol and beta-endorphin when compared with placebo. TSH, triiodothyronine, thyroxine, insulin, glucagon and blood glucose showed no significant differences between both days of the trial. The effect of naloxone on growth hormone and prolactin secretions in obese humans can thus be regarded as a partial normalization. We therefore conclude that the hypothalamic regulatory disturbance of growth hormone and prolactin secretions in the obese could be caused by raised opiate levels.

Topics: Adrenocorticotropic Hormone; Adult; Arginine; beta-Endorphin; Double-Blind Method; Endorphins; Female; Growth Hormone; Humans; Hydrocortisone; Male; Middle Aged; Naloxone; Obesity; Prolactin; Thyrotropin-Releasing Hormone

To investigate the effects of the long-acting opiate antagonist naltrexone on spontaneous human eating behavior, eight moderately obese male paid volunteers were housed in a hospital metabolic unit for 28 days and offered palatable foods ad lib by a platter service method. Under double-blind conditions, equally divided doses of 100, 200 and 300 mg naltrexone, or an acetaminophen placebo, were administered twice daily in tablet form for 3-day periods each, according to a Latin Square design. The doses of naltrexone resulted in decreases of daily caloric intake from placebo level, but these reductions were neither statistically significant nor dose-related. When the averaged effects of the doses were compared to placebo, five subjects showed intake reductions but the overall intake reduction of 301.5 +/- 198.1 kcal/day (mean +/- SEM) was not statistically significant. Naltrexone administration failed to selectively alter intakes of individual meals and snacks or macronutrient consumption patterns. During active drug periods, subjects lost 0.62 +/- 0.22 lb over 3 days, while during the placebo period, subjects gained 0.46 +/- 0.68 lb. However, there was no reliable change of basal metabolic rate as a function of naltrexone administration. The present results, which indicate that naltrexone administration is relatively ineffective in reducing food intake and inducing body weight loss in obese humans, are thus in contrast with reports that administration of opiate antagonist agents promote significant reductions of food intake and attenuations of body weight gain in experimental animals.

Topics: Adult; Basal Metabolism; Body Weight; Clinical Trials as Topic; Drug Administration Schedule; Energy Intake; Feeding Behavior; Humans; Male; Naloxone; Naltrexone; Obesity

Obesity has become a global problem due to its sharply increased prevalence and associated complications. Orexin and opioid signaling can regulate feeding behavior and represent potential therapeutic targets for obesity. In the present experiment, we sought to ascertain the effects of orexin-A and μ-opioid signaling regulation in the basomedial amygdala (BMA) on feeding and investigate the physiology of gastric distension (GD)-responsive neurons in a diet-induced obesity (DIO) and diet-induced obesity resistance (DR) rat model. Intra-BMA infusions of orexin-A increased the firing of BMA GD neurons and increased food intake, and that these effects could be abolished by pretreatment with the orexin-1 receptor (OX-1R) antagonist SB334867, these effects could also be somewhat attenuated by co-administration of naloxone. In the DIO and DR rats, mRNA expression of OX-1R and μ-opioid receptors were increased in the BMA. Our results strongly suggest that orexin-A and opioid signaling in the BMA play a major role in regulating GD neuronal excitability and feeding behavior in obesity.

Topics: Amygdala; Animals; Diet, High-Fat; Eating; Male; Naloxone; Narcotic Antagonists; Neurons; Obesity; Orexin Receptors; Orexins; Rats; Rats, Wistar; Receptors, Opioid, mu

The primary objective of this study was to assess the risk of perioperative anesthesia-related complications in a cohort of obese and non-obese women undergoing outpatient surgical abortion under IV sedation without tracheal intubation.. We performed a retrospective cohort study of all surgical abortions through 22 6/7 weeks' gestation at an outpatient clinic from 2012 to 2013. Women receiving IV sedation were included. Obesity status was defined by the World Health Organization criteria. The primary outcome was the rate of perioperative anesthesia complications defined as tracheal intubation, pulmonary aspiration, hospital transfer for an anesthesia indication, or anesthesia-related adverse events (persistent hypoxemia and allergic reaction). The use of opioid reversal (naloxone) was assessed as a secondary outcome measure. Multivariate analysis for the secondary outcome measure was performed with adjustment for confounding factors.. During the study period, 9348 abortions were performed. Of the 5579 patients who received IV sedation, 1438 (25.8%) were obese, 1707 (30.6%) were in the second trimester, and 851 (15.3%) were ≥17 weeks' gestation. No patients experienced a primary outcome measure. Based on the upper 95% confidence interval (CI) for the sample size, the maximal risk of an anesthesia-related complication is 1 in 1860 procedures. Naloxone use occurred in 13 (0.2%) patients and was not more frequent among obese patients (0.14% vs 0.27%; 95% CI of odds ratio [OR], 0.12-2.36; P = 0.54) or procedures at ≥17 weeks' gestation (0.47% vs 0.19%; 95% CI of OR, 0.76-8.06; P = 0.12). These negative findings should be interpreted with caution, given the limitations of the sample size to assess these secondary outcome measures. Naloxone use was associated with fentanyl doses >200 μg (0.82% vs 0.13%; P = 0.002), an association that remained significant when we controlled for confounding factors (adjusted OR, 5.51; 95% CI, 1.61-18.91). Further analysis revealed that fentanyl dose >200 μg was associated with naloxone use for procedures in the first trimester (incident rate ratio, 9.02; 95% CI, 3.73-21.80) but not in the second trimester (incident rate ratio, 0.92; 95% CI, 0.23-3.70).. Among women receiving IV sedation without tracheal intubation for surgical abortion, anesthesia complications are rare and may not be greater for obese women or procedures at gestational age ≥17 weeks. IV sedation without tracheal intubation may be considered for women undergoing first- and second-trimester surgical abortion; however, the rarity of anesthesia-related complications in our cohort precludes a definitive conclusion regarding the overall safety of IV sedation without tracheal intubation.

Topics: Abortion, Induced; Adolescent; Adult; Ambulatory Surgical Procedures; Anesthesia, Intravenous; Anesthetics, Intravenous; Chi-Square Distribution; Female; Humans; Intubation, Intratracheal; Logistic Models; Multivariate Analysis; Naloxone; Narcotic Antagonists; Obesity; Odds Ratio; Ohio; Postoperative Complications; Pregnancy; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult

The CB1 receptor antagonist, rimonabant, causes weight loss but also produces undesirable psychiatric side effects. We investigated using a combination of rimonabant with the opioid receptor antagonists naloxone and norBNI to treat the metabolic sequelae of long-term high fat diet feeding in mice. This combination has previously been shown to have positive effects on both weight loss and mood related behaviour. Diet-induced obese mice were treated chronically with either low dose rimonabant (1 mg/kg) or the combination of rimonabant, naloxone and norBNI (rim nal BNI). After 6 days of treatment, glucose and insulin tolerance tests were performed and body composition analysed using DEXA. Changes in BAT thermogenesis were assessed using implantable radio telemetry probes. Behavioural responses to acute rimonabant or rim nal BNI were examined in the forced swim test and elevated plus maze. Separately, we assessed shifts in Fos immunoreactivity in response to rimonabant or rim nal BNI. Rim nal BNI was significantly better than rimonabant treatment alone at reducing body weight and food intake. In addition, it improved fasting blood glucose and fat mass. Acute low dose rimonabant did not alter behaviour in either the forced swim test or elevated plus maze. Combination rim nal BNI reversed the behavioural effects of high dose (10 mg/kg) rimonabant in obese mice. Rim nal BNI altered Rimonabant-induced Fos in a number of nuclei, with particular shifts in expression in the central and basolateral amygdala, and insular cortex. This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes. These results indicate that CB1-targeted drugs for weight loss may still be feasible.

Topics: Animals; Body Composition; Cannabinoid Receptor Antagonists; Drug Therapy, Combination; Glucose; Insulin; Male; Mice; Mice, Obese; Naloxone; Narcotic Antagonists; Obesity; Piperidines; Pyrazoles; Rimonabant; Thermogenesis; Treatment Outcome

The adipose tissue-derived hormone leptin may be a primary mediator linking nutritional status and reproduction. The present study used the leptin-resistant obese female Zucker rat to investigate whether leptin signalling is required for normal pulsatile luteinizing hormone (LH) secretion and/or generation of the LH surge. For the pulsatile LH secretion study, an indwelling atrial catheter was implanted and a low dose of oestrogen given as a subcutaneous implant to lean and obese ovariectomized (OVX) Zucker rats. One week following OVX, blood samples were collected every 10 min for 3 h during the morning. Plasma LH concentrations were measured by radioimmunoassay. For the LH surge study, lean and obese OVX rats were given a high dose of oestrogen as a subcutaneous implant. Two days later, rats were given progesterone at 09.00 h to induce a proestrus-like LH surge. Blood samples were collected from an indwelling atrial catheter throughout that and the following day and plasma LH concentrations were measured by radioimmunoassay. LH pulse amplitude and mean LH secretion were profoundly attenuated in obese Zucker rats compared with lean littermates, whereas LH pulse frequency was not significantly different between phenotypes. The opioid receptor antagonist naloxone did not affect the pattern of pulsatile LH secretion in obese rats, suggesting that leptin does not exert its facilitatory effects on LH secretion through an opioidergic pathway. Both lean and obese rats showed characteristic steroid-induced LH surges. It therefore appears that a leptin signal is required for generation of a normal pattern of pulsatile LH secretion, but is not a necessary component of the steroid-induced LH surge.

Topics: Animals; Body Weight; Estrogens; Female; Leptin; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Obesity; Opioid Peptides; Pulsatile Flow; Rats; Rats, Zucker

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Topics: Animals; beta-Endorphin; Eating; Energy Metabolism; Glucose; Homeostasis; Hyperinsulinism; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuropeptide Y; Obesity; Reference Values

To investigate the effect of naloxone, an opioid receptor antagonist, on the release of growth hormone (GH) induced by the growth hormone-releasing hormone (GHRH) in normal-weight and obese women with PCOS in relation to feeding.. Prospective clinical study.. Academic research center.. Seventeen women with PCOS (10 who were normal weight and 7 who were obese) and 14 control women (7 who were normal weight and 7 who were obese).. A GHRH test (50 microg i.v.) and, on a different day, a GHRH test during a naloxone infusion (1.6 mg/h) during fasting. The same tests were repeated after a standard meal.. GH response to GHRH (expressed as the area under the curve [AUC]) in different experimental conditions.. All normal-weight women showed a significantly higher AUC-GH compared with obese women in the fasting state. Normal-weight controls had a decrease in GH response to GHRH after feeding, and naloxone did not reverse the decrease. In obese controls, feeding increased the GH response but naloxone induced a decrease in the AUC. In fasting, normal-weight women with PCOS, naloxone significantly decreased the AUC-GH; in these patients, food intake induced an inhibition of GH response to GHRH, reversed by naloxone infusion. In obese PCOS patients, GH levels did not increase significantly after GHRH stimulation, either in the fasting state or after a meal, and naloxone did not affect these responses.. Factors other than obesity and insulin may be involved in disruption of GH secretion in women with PCOS.

Topics: Adult; Area Under Curve; Body Weight; Eating; Fasting; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Naloxone; Narcotic Antagonists; Obesity; Polycystic Ovary Syndrome; Prospective Studies; Reference Values

Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals.

Topics: Agouti Signaling Protein; alpha-MSH; Animals; beta-Endorphin; Blood Pressure; Body Weight; Dietary Fats; Drug Resistance; Electrophysiology; Female; Heart Rate; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Leptin; Naloxone; Narcotic Antagonists; Obesity; Pressoreceptors; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Opioid; Splanchnic Nerves

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.

Topics: Animals; Eating; Feeding Behavior; Male; Motivation; Naloxone; Narcotic Antagonists; Obesity; Rats; Rats, Zucker

Neuropeptide Y administered intracerebroventricularly and into the paraventricular nucleus of the hypothalamus stimulates feeding and decreases brown adipose tissue thermogenesis. Although specific neuropeptide Y antagonists are not yet available, previous studies had shown that the opioid antagonist naloxone blocked neuropeptide Y-induced feeding when both drugs were injected intracerebroventricularly. We wanted to find out if naloxone injected into specific brain sites would block neuropeptide Y effects on feeding and brown fat thermogenesis. Rats were double injected in specific brain sites with neuropeptide Y and either naloxone or naltrexone (a congener of naloxone). Food intake and brown fat measures were assessed. Naloxone or naltrexone in the paraventricular nucleus weakly decreased paraventricular nucleus neuropeptide Y-induced feeding and did not affect neuropeptide Y-induced reductions in brown fat activity. Peripheral naloxone blocked intracerebroventricular neuropeptide Y-induced feeding and brown fat alterations. Fourth ventricular naloxone decreased paraventricular nucleus neuropeptide Y-induced feeding, and naltrexone given into the nucleus of the solitary tract blocked paraventricular nucleus neuropeptide Y-induced alterations in feeding and brown fat. These data indicate that neuropeptide Y in the paraventricular nucleus may act on feeding and brown fat thermogenesis through opioidergic pathways in the nucleus of the solitary tract.

Topics: Adipose Tissue, Brown; Animals; Brain; Energy Metabolism; Feeding Behavior; Male; Naloxone; Naltrexone; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Solitary Nucleus

Acute administration of long-acting general opioid antagonists reduces body weight and food intake in rats. In contrast, chronic administration of short-acting general opioid antagonists produces transient effects. The present study evaluated whether chronic central administration of selective long-acting antagonists of mu (beta-funaltrexamine, BFNA, 20 micrograms), mu1 (naloxonazine, 50 micrograms), delta1 ([D-Ala2,Leu5,Cys6]-enkephalin, DALCE, 40 micrograms), delta2 (naltrindole isothiocyanate, NTII, 20 micrograms) or kappa (nor-binaltorphamine, NBNI, 20 micrograms) opioid receptor subtypes altered weight and intake of rats exposed to a palatable diet of pellets, fat, milk and water, relative to pellet-fed and diet-fed controls. Diet-fed rats receiving chronic vehicle injections significantly increased weight (7-10%) and intake over the 11-day time course. Weight was significantly reduced over the time course in rats administered either BFNA (9%), naloxonazine (12%), DALCE (7%) or NTII (6%). Initial weight reductions failed to persist following chronic NBNI. All antagonists chronically reduced fat intake, but did not systematically alter total intake, pellet intake or milk intake relative to the pattern of weight loss. These data indicate that central mu, mu1, delta1, delta2, and, to a lesser degree, kappa receptors mediate long-term opioid modulation of weight even in animals maintained on diets that ultimately result in dietary obesity.

Topics: Animals; Body Weight; Dietary Fats; Eating; Male; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Rats; Rats, Sprague-Dawley; Time Factors

Topics: Adult; Atrial Natriuretic Factor; beta-Endorphin; Blood Glucose; Female; Humans; Insulin; Male; Middle Aged; Naloxone; Obesity

This study evaluated the modulatory role of endogenous opioids on ventilation in young and mature, lean and obese male Zucker rats. Naloxone, an opioid receptor antagonist, and saline (control) were administered subcutaneously to awake rats, and ventilation in air and in response to an hypoxic and an hypercapnic gas challenge measured. In response to naloxone young, obese but not lean rats exhibited a marked increase of ventilation in all three conditions. Older obese Zucker rats that were morbidly obese breathed at a frequency of over 200 breaths per minute and showed only a modest increase of ventilation in response to naloxone. Older lean rats increased ventilation with naloxone only when exposed to hypercapnia. Unlike the stimulatory effects hypoxia and hypercapnia had on ventilation in older, lean rats, the ventilatory responses of the obese, older rats to hypoxia and to hypercapnia were blunted. We conclude that the obese Zucker rat may be a good animal model to assess how chest wall loading and endogenous opioids interact in the development of ventilatory control abnormalities.

Topics: Animals; Disease Models, Animal; Hypercapnia; Hypoxia; Male; Naloxone; Obesity; Opioid Peptides; Pulmonary Ventilation; Rats; Rats, Zucker; Respiration

Naloxone is an opioid antagonist used frequently in studies of appetite regulation in lean and obese animals and humans. Body condition may affect plasma and tissue distribution of injected naloxone and thus confound interpretation of responses to naloxone in lean compared with obese subjects. The objective of this experiment was to determine the effect of dietary obesity per se on the pharmacokinetic behavior of iv-injected naloxone (3 mg/kg) in lean (46 kg body weight) and dietary obese (77 kg body weight) sheep that were maintained at equilibrium weight. To this end, an HPLC procedure combined with electrochemical detection was developed for measuring naloxone in sheep plasma. Naloxone disappearance from plasma followed an apparent first-order process, the kinetics of which were described best using a two-compartment open model. Components of the biexponential equations describing the plasma concentration (C)-time (t) curves for naloxone disappearance in lean (Ct = 1814e(-0.190t) + 413e(-0.017t)) and obese (Ct = 2282e(-0.282t) + 573e(-0.018t)) sheep were similar (p > 0.05). Mean (+/- SE) elimination half-lives for naloxone in lean (42.7 +/- 4.6 min) and obese (44.3 +/- 10.2 min) sheep were similar (p > 0.05). Volume of distribution of naloxone (Vd) was extensive but also similar (p > 0.05) in lean (5.6 +/- 0.9 L/kg) and obese (4.1 +/- 0.6 L/kg) sheep. Naloxone was distributed extensively throughout the body fluids and trapped or stored in significant amount in extravascular tissues because the naloxone Vd greatly exceeded 100% of body weight in both lean (557 +/- 86 mL/100 g) and obese (413 +/- 58 mL/100 g) sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Fluid Compartments; Chromatography, High Pressure Liquid; Diet; Disease Models, Animal; Female; Naloxone; Obesity; Sensitivity and Specificity; Sheep

This paper has tested the hypothesis that patients with hypothalamic obesity have altered mechanisms controlling insulin secretion when compared to obese patients without hypothalamic injury. Fasting glucose and insulin values were significantly higher in the morning than in the afternoon in the six control obese patients, but there was no diurnal difference in the six patients with hypothalamic obesity (n=6). The control obese subjects showed a diurnal variation in glucose-stimulated insulin secretion, whereas the patients with hypothalamic obesity did not, suggesting that hypothalamic injury had destroyed diurnal rhythms. Naloxone, an opioid antagonist, acutely suppressed fasting insulin in the six patients with essential obesity but had little effect on fasting insulin in the three patients with hypothalamic obesity or in five normal-weight controls. Naloxone increased insulin sensitivity in the obese control patients, but did not affect either insulin secretion or insulin sensitivity in patients with hypothalamic obesity or in normal weight subjects. Our results support the conclusion that hypothalamic obesity disrupts diurnal rhythms, with the suggestion that opioid peptides affect insulin secretion differently in patients with essential obesity as compared to normal weight subjects or those with hypothalamic obesity.

Topics: Adolescent; Adult; Blood Glucose; Body Height; Body Mass Index; Body Weight; Carbohydrates; Case-Control Studies; Circadian Rhythm; Female; Glucose; Glucose Tolerance Test; Humans; Hypothalamic Diseases; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Male; Naloxone; Narcotic Antagonists; Obesity; Time Factors

In order to investigate the relationships between glucose metabolism, insulin secretion and endogenous opioids in obese patients, we have studied the effects of a naloxone infusion on insulin and C-peptide release after a normal meal (800 kcal) eaten at 12.00 hr in 16 obese women, aged 20-61 yr, with a BMI ranging from 25 to 37.2 kg/m2, with normal glucose tolerance (Group 1) and with NIDDM (Group 2). Naloxone was administered in a bolus of 1.6 mg i.v., followed by a continuous infusion of 4 mg in 2 hr starting immediately after feeding. In Group 1 naloxone infusion significantly increased the glucose levels, but insulin secretion was unaffected. In Group 2, naloxone infusion failed to modify significantly the postprandial levels of glucose, insulin and C-peptide. Therefore, in our study naloxone infusion seems to have beta-endorphin-like effects in non-diabetic obese subjects by increasing their glycemic levels, with no evidence of expected insulin decrease. In diabetic obese patients we observed a trend towards decrease in glycemic values during naloxone infusion, as expected, due to insulin plasma levels increase. By these data we can hypothesise a complex regulatory role of opioids in metabolic balance in obesity. In diabetic patients, naloxone can improve the surviving insulin secretion with better glucose tolerance. In non-diabetic subjects naloxone exerts its effects, probably, on peripheral organs.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Infusions, Intravenous; Insulin; Middle Aged; Naloxone; Obesity

The concentrations of beta-endorphin, ACTH, insulin (IRI), glucagon (IRG), cortisol and growth hormone were determined by radioimmunoassay during oral glucose tolerance test (OGTT) performed in 13 obese patients with normal glucose tolerance and without arterial hypertension. The test was performed in random, before and after intravenous administration of 0.8 mg of naloxone. Six persons with normal body weight served as controls. Higher basal concentrations of beta-endorphin and significant increase in beta-endorphin levels during OGTT, without concomitant increase in ACTH concentrations, have been found in obese patients. No effect of naloxone on beta-endorphin liberation during OGTT was observed, though the drug caused lowering in maximal increment of beta-endorphin and paradoxically lowered the concentrations of ACTH and cortisol. The basal concentrations of beta-endorphin did not correlate with the concentrations of insulin, ACTH, cortisol and growth hormone. Elevated concentrations of insulin, lowered concentration of growth hormone and normal levels of glucose and glucagon were observed in basal conditions, and excessive responses of insulin, glucose and glucagon were observed in obese patients during OGTT. Naloxone lowered insulin response and inhibited the fall of growth hormone during OGTT but did not influence the concentrations of glucose and glucagon. No correlation was found during OGTT after naloxone between insulin and beta-endorphin, ACTH or cortisol, whereas negative correlation was observed between insulin and growth hormone. The obtained results suggest that the elevated concentrations of beta-endorphin in simple obesity may be of both hypophyseal and peripheral origin. Hyper-beta-endorphinemia observed in obesity is probably not directly responsible for hyperinsulinemia, it may, however, be responsible for lower sensitivity of tissues to the action of insulin.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Female; Glucose Tolerance Test; Growth Hormone; Humans; Hydrocortisone; Insulin; Male; Middle Aged; Naloxone; Obesity; Radioimmunoassay

To evaluate the involvement of endogenous opiates in the pathophysiology of the hyperinsulinism in patients affected by polycystic ovary disease by administering naloxone and naltrexone. We also studied the hormonal status following long-term opioid antagonist administration.. Twenty-one women affected by polycystic ovary disease participated in the study. An oral glucose tolerance test (GTT) was performed at baseline and repeated after short-term naloxone infusion and after 6 weeks of naltrexone administration. Plasma glucose and insulin levels were evaluated in all samples. Gonadotropins, sex hormone-binding globulin, and androgen levels were determined initially and after the naltrexone treatment.. None of the patients showed any alteration of glucose tolerance. Based on the insulin response to the GTT, the patients were classified as normo- or hyperinsulinemic. Opioid antagonist administration significantly reduced the insulin response to the GTT in hyperinsulinemic patients, without affecting their glycemic levels. In normoinsulinemic patients, glucose plasma levels were increased whereas insulin levels were not modified by the treatments. Gonadotropin and androgen plasma concentrations were not modified after naltrexone administration.. This work supports a role for the endogenous opiates in the regulation of exaggerated insulin secretion in patients with polycystic ovary disease. The reduction of insulin secretion failed to demonstrate any hormonal modification in such hyperandrogenized patients.

Topics: Adult; Endorphins; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Hyperinsulinism; Insulin; Naloxone; Naltrexone; Obesity; Polycystic Ovary Syndrome; Time Factors

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Female; Humans; Hydrocortisone; Male; Naloxone; Obesity

The present study was carried out to establish whether the low arginine vasopressin (AVP) and oxytocin (OT) responses to insulin-induced hypoglycemia observed in obese men was due to alteration of the opioid control of posterior pituitary function. For this purpose, the AVP and OT releasing effect of insulin (0.15 IU/kg bw)--induced hypoglycemia was tested in eight normal weight men and in 10 age-matched obese subjects, without and with the previous treatment with the specific opioid receptor antagonist naloxone (3 mg in an iv bolus). In a control study, naloxone was given alone to the same subjects. Obese men showed similar basal glucose, AVP and OT levels, which remained unmodified after treatment with naloxone alone. Insulin induced a similar decrement of blood glucose levels in all subjects, with a nadir at 30 min. Plasma levels of AVP and OT rose strikingly in normal and obese subjects with mean peak responses at 30 min for AVP and at 45 min for OT. However, both AVP and OT responses were significantly lower in obese than in control subjects. Pretreatment with naloxone did not modify the AVP and OT responses to hypoglycemia in normal weight subjects, whereas it significantly enhanced both hormonal responses in obese subjects. In the presence of naloxone normal controls and obese subjects showed similar responses of both AVP and OT to hypoglycemia. These data indicate that an abnormal activity of endogenous opioids might account for the hypothalamic posterior pituitary dysfunction, which is responsible for the low AVP and OT responses to insulin-induced hypoglycemia in obesity.

Topics: Adult; Arginine Vasopressin; Blood Pressure; Hematocrit; Humans; Hypoglycemia; Insulin; Male; Naloxone; Obesity; Osmolar Concentration; Oxytocin

The effect of naloxone (opioid receptor blocker) on the impairment of growth hormone (GH) release after clonidine (alfa 2-adrenergic agonist) was investigated in 10 volunteer obese subjects. The patients (4 males and 6 females, 16-22 year old) with fat excess (15 +/- 2 kg) estimated by bioelectrical impedance analysis (BIA) were studied repeatedly. The patients, were perfused by a slow saline infusion. 30 min later they received a bolus dose of clonidine (150 micrograms p.o.), followed 30 min later by a bolus dose of naloxone (10 mg i.v.) or a corresponding volume of isotonic sodium cloride (I.S.) for control. No significant changes occurred in blood GH concentration after clonidine administration and naloxone did not induce GH response at clonidine. These results suggest that in obese subjects the impairment of GH release after clonidine is not mediated via receptors sensitivity to naloxone.

Topics: Adolescent; Adult; Clonidine; Female; Growth Hormone; Humans; Male; Naloxone; Obesity

The effects of opiate receptor antagonist naloxone on growth hormone (GH) release after growth hormone-releasing hormone (GHRH) administration were investigated, before or after feeding, at 13.00 h, in 20 obese women and in 10 normal women. When GHRH was administered to obese women before a meal at lunch time, the mean peak plasma GH levels were very low, while plasma GH responses significantly increased after feeding. Naloxone, infused at a rate of 1.6 mg/h starting 1 h before GHRH administration (50 micrograms i.v. as a bolus), was capable of inhibiting GH release induced by administration of GHRH after feeding. On the contrary, naloxone did not induce significant variations on the fasting GHRH-induced GH release. In normal women, naloxone did not significantly modify the GH response to GHRH, both before and after lunch. The inhibitory effect of naloxone indicates that in obese women there is an increased opioid activity, which could represent an abnormal response of the gastrointestinal tract to food ingestion.

Topics: Adult; Eating; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Naloxone; Obesity; Receptors, Opioid

Recent studies suggest that opioid peptides may influence the secretion of pituitary gland hormones. Since obese patients often show impaired growth hormone (GH), prolactin (PRL) and cortisol responses to stimuli and raised beta endorphin levels, the opioid regulation of such hormone secretion could be different from that in normal weight subjects. In order to verify this hypothesis we studied the effect of iv naloxone, an opiate receptor antagonist, on GH, PRL and cortisol response to insulin-induced hypoglycemia in 9 obese female subjects. Seven normal weight females were used as control group. A control test using saline showed that the PRL and GH responses to insulin stress were impaired in obese subjects, whereas no difference was seen in the cortisol response. Naloxone did not modify the PRL and GH response but provoked a rise in the cortisol response in both obese and normal weight subjects. These findings suggest that while the opioid peptides do not play an important role in regulating the GH and PRL response to insulin hypoglycemia, they influence the cortisol response. In obese patients the impairment in GH and PRL response to stimuli cannot be related to alterations in opioid peptide regulation.

Topics: Adolescent; Adult; Blood Glucose; Body Weight; Female; Growth Hormone; Humans; Hydrocortisone; Insulin; Middle Aged; Naloxone; Obesity; Prolactin

The effects of endogenous opiates on insulin response to oral glucose load were studied in obese subjects and in lean healthy volunteers. None of these having a family diabetes. After 3 days on an 1,800 cal./m2, 40% carbohydrate diet all subjects underwent two standard 75 g oral glucose tolerance tests (OGTT), one of which was accompanied by an i. v. administration of 10 mg of, an antagonist of opiates, the naloxone. In one group of obese impaired oral glucose tolerance test occurred. All obese, but not the lean healthy volunteers, showed: 1) increased basal plasma insulin levels, 2) higher insulin response to OGTT, 3) a decrease in insulin response to OGTT after naloxone administration, with significant differences at 60 min (p less than 0.01) and 90 min (p less than 0.025). In none of the subjects significant differences were observed in blood glucose levels after OGTT plus naloxone administration. These data suggest that increased endogenous opiates may affect insulin response to glucose in obese with impaired or normal oral glucose tolerance test. At present there seems to be no satisfactory explanation for unchanged blood glucose levels during OGTT with and without naloxone despite a decrease in insulin secretion in the obese patients.

Topics: Adolescent; Adult; Endorphins; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Naloxone; Obesity

To determine whether endogenous opiates mediate hyperactivity in food restricted hamsters and serotonergic fibers innervating the hippocampus mediate hypoactivity in obese hamsters, food restriction and high-fat diet supplementation were used to produce significant body fat changes (8 vs. 21%). The levels and pattern of spontaneous running were examined after IP saline or naloxone HCl (20 mg/kg) and following the infusion of vehicle and 5,7-dihydroxytryptamine creatine sulfate (4 micrograms/2 microliters) into rostromedial septum of mature female hamsters. Septum-medial preoptic area (POA), hippocampus, hypothalamus, and cortex were dissected from the three groups as well as from two additional groups of hamsters receiving vehicle or neurotoxin. Concentrations of serotonin, norepinephrine, and dopamine were measured in these tissues by HPLC method. Fat-fed hamsters were hypoactive relative to food-restricted hamsters. Naloxone had no significant effect on running behavior. Serotonin neurotoxin increased the running activity of fat-fed hamsters to the level displayed by control hamsters by increasing the number of runs, the total activity level, the speed of running and by decreasing the duration of pauses. Neurotoxin led to selective deletion of serotonin in the hippocampus (77%) and parietal cortex (50%). Serotonergic fibers innervating the hippocampus thus appear to mediate the hypoactivity that is induced by dietary obesity in mature hamsters. Since serotonin mediates some other manifestations of aging, and slow weight increases characterize mid-portion of hamster life span, we hypothesize that serotonergic mediation of hypoactivity is another manifestation of aging.

Topics: 5,7-Dihydroxytryptamine; Aging; Animals; Body Weight; Brain Chemistry; Cricetinae; Dietary Fats; Dihydroxytryptamines; Dopamine; Fasting; Female; Hippocampus; Mesocricetus; Motor Activity; Naloxone; Norepinephrine; Obesity; Serotonin

In order to evaluate the role of opiate, dopaminergic and adrenergic systems in the mechanism of hypothalamo-pituitary disturbances in obesity, 9 obese women and 14 healthy women were investigated. Serum GH, LH, beta-endorphin and cortisol concentrations were measured after administration of clonidine, an alpha 2-adrenergic receptor agonist, and naloxone, an opiate antagonist. Additionally, PRL levels were measured after administration of the dopamine receptor blocker metoclopramide. An impaired GH response to clonidine and naloxone was found in obese women. However, a marked increase in beta-endorphin was observed in obese patients after clonidine administration. Naloxone did not cause any significant change in beta-endorphin release. Neither clonidine nor naloxone induced any change in LH release. Serum PRL concentrations in response to metoclopramide were significantly higher in obese patients than in healthy women.. Disturbed activity in opiate, adrenergic, and dopaminergic systems may be of pathogenetic importance in a hypothalamo-pituitary dysfunction in obesity. The occurrence of hypothalamic amenorrhoea as well as the presence of abnormalities of the central nervous system regulation of GH, PRL, ACTH, cortisol, insulin and vasopressin output might point to a generalized hypothalamo-pituitary dysfunction in obesity.

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; beta-Endorphin; Clonidine; Female; Growth Hormone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Metoclopramide; Naloxone; Obesity; Prolactin; Receptors, Dopamine; Receptors, Opioid

Naloxone, an opiate antagonist, was given as an intravenous bolus (5 mg) in both lean and obese healthy subjects. In lean people, there was a slight trend for insulin and C-peptide concentrations to decrease below baseline values with no glucose change. Obese subjects showed an exaggerated suppression of insulin and C-peptide and a slight decrease of glucose. Glucagon was suppressed in both groups. An infusion of human beta-endorphin (0.05 mg/h) produced only minor changes in plasma glucose, insulin, glucagon, and C-peptide concentrations in lean subjects, but caused marked increments in obese. Glucagon rose in both groups, but its response was greater in obese subjects. A ten-day treatment with naloxone (1.2 mg twice a day) did not change the metabolic and hormonal responses to an oral glucose load (75 g) in lean but significantly inhibited the insulin and C-peptide responses to glucose in obese people. These results suggest that an increased opiate drive to the pancreatic beta-cell and an increased responsiveness of insulin to beta-endorphin are present in human obesity.

Topics: Adult; beta-Endorphin; Blood Glucose; C-Peptide; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Islets of Langerhans; Male; Naloxone; Obesity

Prader-Willi syndrome (PWS) is characterized by morbid obesity and abnormal appetite. It has been suggested that appetite is reduced by the administration of the opioid antagonist, naloxone. This has led to the hypothesis that appetite disturbance is a consequence of an abnormal hypothalamic response to appetite effects of endogenous opiates and opiate antagonist may be a useful treatment. To characterize the feeding patterns of PWS children and test this hypothesis, we administered an appetite test to 10 PWS children and 9 obese control children. We also examined the effects of naloxone on eating behavior of the children with PWS. While initial rate of eating did not differ, the PWS group showed a much delayed satiety resulting in a longer period of food intake. No difference in food intake was observed with naloxone (1.6 mg im, 30 min before the feeding test) treatment as compared with saline treatment.

Topics: Adolescent; Appetite; Child; Eating; Feeding Behavior; Female; Humans; Male; Naloxone; Obesity; Prader-Willi Syndrome; Time Factors

To test the hypothesis that endogenous opiates play a role in the etiology of the sleep apnea syndrome, we administered naloxone, an opiate antagonist, to ten obese humans with sleep apnea. On two separate nights we measured the frequency and severity of sleep apnea during naloxone infusion vs saline control infusion. The number of oxyhemoglobin desaturation episodes was not significantly lowered but the average maximal oxyhemoglobin desaturation fell significantly (P less than 0.01) with naloxone. The desaturation index (average maximal oxyhemoglobin desaturation times desaturations per hour) fell by 21 percent (P less than 0.05) on the night of naloxone infusion. Nine of the ten patients had a lower desaturation index with naloxone. REM sleep decreased by 80 percent (P less than 0.05) in the subjects in whom it was measured. We conclude that opiate antagonists hold promise in the treatment of sleep apnea and that the endogenous opiate system may be involved in the production of sleep apnea.

Topics: beta-Endorphin; Endorphins; Female; Humans; Male; Naloxone; Obesity; Sleep Apnea Syndromes; Sleep, REM

Nondeprived adult rats were familiarized with a highly palatable diet (powdered small animal diet mixed with sweetened condensed milk and water). The palatability of food was such that it induced vigorous feeding responses, 15-20 g food consumed within the first 30 min of access. In partially-satiated male rats, the kappa receptor agonists EKC and U-50,488 (subcutaneously administered) produced large increases in food consumption in the first 30 min of access, post-injection. In experiments with naloxone and WIN 44,441-3, we found that the effects of naloxone (0.01-10 mg/kg; S.C.) were crucially dependent on the sex and dietary history of the animals. Male, obese rats were most sensitive to naloxone's anorectic effect. Lean females were completely insensitive. WIN 44,441-3 (0.01-10 mg/kg, S.C.) had no effect on food intake in any group of animals.

Topics: Animals; Appetite Depressants; Azocines; Diet; Feeding Behavior; Female; Male; Naloxone; Obesity; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Sex Factors

Topics: Adult; Energy Intake; Female; Humans; Male; Middle Aged; Naloxone; Obesity; Random Allocation; Receptors, Opioid

Topics: Adolescent; Adult; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Naloxone; Obesity; Receptors, Opioid

Young and mature, genetically obese and non-obese, spontaneously hypertensive rats (SHR) were injected with saline (controls) or naloxone for 12 weeks. Naloxone stilled the hyperphagia to a normal intake in the obese SHR (Obese/SHR) so that young Obese/SHR did not develop their usual massive obesity and mature Obese/SHR that had become massively obese were reduced to leanness. The naloxone-treated young, obese and non-obese SHR (controls) exhibited marked reduction of the weight of their pituitary and adrenal glands, whereas the pituitary and adrenal glands of naloxone-treated mature, obese and non-obese/SHR were greatly increased in weight. The elevated systolic blood pressure of the obese and non-obese rats was reduced after chronic treatment with naloxone. Naloxone treatment caused reduction of blood ACTH, corticosterone, and beta endorphin levels but elevated growth hormone levels. The characteristic hyperinsulinemia, hyperlipidemia, hyperglycemia, elevated BUN levels, and the Cushingoid spectrum of degenerative changes found in Obese/SHR did not appear in naloxone-treated rats.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Body Weight; Corticosterone; Cushing Syndrome; Disease Models, Animal; Endorphins; Female; Growth Hormone; Male; Naloxone; Obesity; Organ Size; Pituitary Gland; Rats; Rats, Inbred SHR; Rats, Inbred Strains

Opiates, morphine and [D-Ala2-D-Leu5]-enkephalin (DADLE), inhibited the K+-stimulated release of cholecystokinin (CCK) from the hypothalamus of both Zucker obese (fa/fa) and lean (Fa/-) rats, in vitro. Morphine and DADLE did not inhibit the K+-stimulated release of CCK from frontal cortex from either strain. The opiates did not affect basal efflux of CCK and their effects were all blocked by equimolar concentrations of naloxone. These studies indicate a regional specificity for the effect of opiates on CCK release, and may provide evidence for a cellular mechanism by which endogenous opiates modulate feeding behavior.

Topics: Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Frontal Lobe; Hypothalamus; Morphine; Naloxone; Obesity; Potassium; Rats; Rats, Zucker; Sincalide

The effects of naloxone on feeding patterns were studied in both obese and lean Zucker rats during both light and dark phases of the diurnal cycle. Eight female obese (471 +/- 9 g) and lean (225 +/- 6 g) Zucker rats were trained to bar press for food. They were administered 0, 0.5, 1.0 or 2.0 mg/kg naloxone at the initiation of the light or dark phase of the diurnal cycle and feeding behavior was recorded for the subsequent 12 hr using an automated real-time data collection system. First meal size and duration were decreased and first postmeal interval was increased by naloxone and responses did not vary with phenotype or phase of the diurnal cycle. Naloxone decreased food intake during the 12-hr period by decreasing average meal size but meal frequency was not affected. Overall, the feeding behavior responses of obese rats to naloxone were greater than those of lean rats, supporting the hypothesis of an association between opioid peptides and obesity. Opioid involvement in diurnal control of food intake is also supported by the greater responses generally demonstrated in the light compared with dark phases.

Topics: Animals; Drinking Behavior; Endorphins; Energy Intake; Feeding Behavior; Female; Light; Naloxone; Obesity; Periodicity; Rats; Rats, Zucker

Recent reports have indicated that genetically obese hyperinsulinemic mice (ob/ob) and Zucker rats (fa/fa) compared with their lean controls have elevated levels of pituitary and plasma B-endorphins, opiates that can stimulate insulin secretion. In this study we have measured opiate levels by a radio-receptor assay in gastro-intestinal tissues and pancreas in ob/ob and fa/fa animals and their controls. Ob/ob mice showed significantly higher levels than control mice (+/+) in most gastro-intestinal tissues and pancreas. Levels in fa/fa rats did not differ from their controls. Radioimmunoassay of pancreas for B-endorphins, revealed higher levels in ob/ob vs +/+ mice, while there was no difference in the obese and lean rats. Fasting tended to decrease gastro-intestinal opioids in mice, while B-endorphin levels rose. It is concluded that opiates may play a significant role in the obesity of the ob/ob mouse and that this genetic obesity differs from that in Zucker rats.

Topics: Animals; Chromatography; Digestive System; Endorphins; Enkephalin, Leucine; Fasting; In Vitro Techniques; Insulin; Insulin Secretion; Male; Mice; Mice, Obese; Naloxone; Obesity; Pancreas; Radioimmunoassay; Radioligand Assay; Rats; Rats, Zucker; Tissue Distribution; Tissue Extracts

Opioids are proposed to play a role in the control of food intake since administration of opioids increase food intake while administration of opioid antagonists decrease food intake. In these experiments responses to a new opioid antagonist, nalmefene, were measured in Zucker obese and lean rats. In obese male rats 1 mg/kg nalmefene decreased the size of the first meal after a 10-hr fast and decreased 14-hr food intake, indicating nalmefene is relatively long-acting. Administration of 1 mg/kg nalmefene daily for 7 days decreased average meal size and daily food intake and increased meal frequency; feeding responses on day 7 were similar to those on day 1, suggesting a lack of development of tolerance. Food and water intake and weight gain during a 3-week treatment period were decreased more in lean rats by low doses of nalmefene (up to 0.25 mg/kg) and more in obese rats by higher doses of nalmefene (0.50 mg/kg). These responses to a new opioid antagonist further support a possible role for opioids in the control of food intake.

Topics: Animals; Appetite; Appetite Depressants; Body Weight; Drinking; Energy Intake; Female; Male; Naloxone; Naltrexone; Obesity; Rats; Rats, Zucker; Time Factors

The present studies tested the effect of acute and chronic administration of naloxone on food intake of lean and genetically obese (ob/ob) mice. Acute administration of naloxone, a drug which blocks opiate receptors, produced a greater reduction of food intake in obese (ob/ob) mice than in the lean littermates. For chronic experiments with naloxone, the daily feeding period was shortened to eight hours and two injections of naloxone were given four hours apart. With this procedure of scheduled-feeding the food intake of both lean and obese mice was depressed during the first hour after injecting naloxone. However, beginning on the second day of treatment, the lean mice began to eat more food than the untreated controls during the eight hour feeding period. Food consumption by lean mice reached values 140 to 200% above the control levels between the fourth and sixth day. In the obese mice the rise in food intake was more gradual and did not reach 200% of the control value until the sixth day. Body weight changes reflected the changes in food intake. In contrast to naloxone, chronic treatment with morphine lowered food intake and blocked the stimulatory effect of naloxone. Our findings suggest that endogenous opioids may play a role in signalling satiety and in regulating long-term energy balance.

Topics: Animals; Body Weight; Diet; Eating; Energy Intake; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Morphine; Naloxone; Obesity; Receptors, Opioid; Time Factors

Studies in rodents suggest the possibility of an association between elevated endogenous opiate activity and overeating and obesity. One measure of elevated opiate activity is sensitivity to the opiate antagonist naloxone. Seven massively obese human subjects showed no subjective or physiological sensitivity to large intravenous doses of naloxone. This finding fails to support a relationship between elevated endorphin activity and human obesity.

Topics: Arousal; Eating; Endorphins; Female; Humans; Male; Naloxone; Obesity; Receptors, Opioid

Topics: Blood Glucose; Dose-Response Relationship, Drug; Eating; Female; Humans; Insulin; Male; Naloxone; Obesity

Topics: Adrenocorticotropic Hormone; Endorphins; Humans; Male; Middle Aged; Naloxone; Obesity

The role of beta-endorphin in the development of several obesity syndromes was examined. Adult female hooded rats received ventromedial hypothalamic lesions, dorsolateral tegmental lesions, parasagittal hypothalamic knife cuts, intraventricular 5,7-dihydroxytryptamine, ovariectomy, control surgery, or were deprived to 75% of normal body weight. Dose-dependent suppression of food intake by the opiate antagonist naloxone (0.5, 1.8, 6.8, or 25.0 mg/kg, ip) was measured during once-daily 4-h food access periods. No difference was found among the groups at any dose. Pituitary beta-endorphinlike immunoreactivity (BELI) was substantially decreased in knife-cut rats, but was unaltered by other treatments. Obesity had no effect on BELI. In another experiment, rats made obese by prolonged maintenance on palatable foods had elevated pituitary BELI levels. Feeding mechanisms involving opioid peptides do not appear to be of etiological significance in the syndromes examined.

Topics: 5,7-Dihydroxytryptamine; Animals; beta-Endorphin; Castration; Endorphins; Feeding Behavior; Female; Hypothalamus; Naloxone; Obesity; Pituitary Gland; Rats

Naltrexone, an opiate antagonist, was administered to young obese (ob/ob) and lean mice for five weeks. Animals had continuous access to food and received 10 mg/kg SC twice daily with equivalent volumes of saline given to controls. The effects on body weight, and pituitary and plasma levels of beta-endorphin-like material were measured. Naltrexone-injected obese animals gained weight more slowly over the first three weeks while the weight gain of lean animals was not affected by naltrexone. Plasma levels of beta-endorphin were shown to be significantly higher in untreated ob/ob mice and this difference increased with age (4-20 weeks). With naltrexone treatment, plasma levels in +/? mice rose and exceeded those in ob/ob. Saline treatment appeared to be a stress, and pituitary beta-endorphins rose 4-6 fold in ob/ob compared with +/?. While naltrexone reduced the levels of ob/ob pituitary towards normal, no effect on beta-endorphin levels in pituitary of lean mice was obtained. In vitro studies of effects of the opiate antagonists, naloxone, on insulin secretion by isolated islets provided additional evidence of resistance of lean mice to naloxone relative to ob/ob. (IRI secretion fell only in naloxone treated ob/ob islets). These observations support the contention that this form of genetic obesity is characterized by elevated endogenous opiate levels and an increased sensitivity to opiate antagonists such as naltrexone or naloxone.

Topics: Animals; beta-Endorphin; Body Weight; Endorphins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Obese; Naloxone; Naltrexone; Obesity; Pituitary Gland; Receptors, Opioid

Intraperitoneal injections of naloxone hydrochloride (1, 2, 4, and 8 mg/kg) suppressed food intake in both normal and hypothalamic obese rats maintained on a 4-hr per day feeding schedule. The decrease in feeding was more pronounced in the animals with ventromedial hypothalamic lesions. Appetitively motivated feeding, i.e., the consumption of sweetened milk under nondeprived conditions, was also suppressed by naloxone, but there was no reliable difference between groups. It is concluded that opiate receptors located in the ventromedial hypothalamus are not essential for the effects of opiate agonists and antagonists on feeding behavior.

Topics: Animals; Feeding Behavior; Female; Food Deprivation; Hypothalamus; Naloxone; Obesity; Rats

Small doses of the opiate antagonist naloxone selectively abolished overeating in genetically obese mice (ob/ob) and rats (fa/fa). Elevated concentrations of the naturally occurring opiate beta-endorphin were found in the pituitaries of both obese species and in the blood plasma of the obese rats. Brain levels of beta-endorphin and Leu-enkephalin were unchanged. These data suggest that excess pituitary beta-endorphin may play a role in the development of the overeating and obesity syndrome.

Topics: Animals; Disease Models, Animal; Eating; Endorphins; Feeding Behavior; Female; Male; Mice; Mice, Obese; Naloxone; Obesity; Pituitary Gland; Rats

The anesthesiologist uses a wide spectrum of drugs, including inhalational general anesthetics, barbiturates, benzodiazepines, narcotics analgesics and their antagonists, and neuromuscular blocking drugs. All of these drugs in sufficient dose impair the ventilatory response to chemical stimuli, and may cause inadequate gas exchange. The effect of depression of ventilatory control depends on the magnitude of depression and the coexistence of functional abnormalities in the respiratory system. The functional abnormalities are the result of preexistent pulmonary disease or other disease processes that impair respiratory function, the anticipated effects of major surgery (e.g., pulmonary resection), and the complications of anesthesia and surgery. From a functional viewpoint, the mechanisms of the effects of these disease processes on ventilatory control are: (1) interference with the neurophysiological control of automatic ventilation; (2) impairment of peripheral or central chemoreceptor function; (3) impairment of respiratory muscle function; (4) increase in the mechanical load to breathing as a result of increased resistance or decreased compliance of the respiratory system; and (5) increase in the ventilatory requirements as a result of ventilation/blood flow maldistribution, metabolic acidosis, or increased metabolic rate. As a result of current trends in the use of multiple drugs and controlled ventilation during anesthesia, the patient is at greatest risk during the early postoperative period in the recovery room. In addition to the functional abnormalities described above, the probability of impaired gas exchange and respiratory failure is increased as a result of impaired metabolism and elimination of drugs as a result of hepatic and renal insufficiency, and acute changes in acidbase status, which alter the ionization and distribution of drugs.

Topics: Anesthetics; Anti-Anxiety Agents; Autonomic Nervous System; Barbiturates; Benzodiazepines; Carbon Dioxide; Fentanyl; Halothane; Humans; Hyperthyroidism; Hypoxia; Lung Diseases, Obstructive; Meperidine; Methoxyflurane; Morphine; Naloxone; Neuromuscular Blocking Agents; Neuromuscular Diseases; Obesity; Pulmonary Edema; Pulmonary Fibrosis; Respiration; Scoliosis