beta-funaltrexamine and Body-Weight

To test the hypothesis that micro-opioid receptor signaling in the nucleus accumbens contributes to hedonic (over)eating and obesity. To investigate the effects of chronic micro-opioid antagonism in the nucleus accumbens core or shell on intake of a palatable diet, and the development of diet-induced obesity in rats.. Chronic blockade of micro-opioid receptor signaling in the nucleus accumbens core or shell was achieved by means of repeated injections (every 4-5 days) of the irreversible receptor antagonist beta-funaltrexamine (BFNA) over 3-5 weeks. The diet consisted of either a choice of high-fat chow, chocolate-flavored Ensure and regular chow (each nutritionally complete) or regular chow only. Intake of each food item, body weight and body fat mass were monitored throughout the study.. The BFNA injections aimed at either the core or shell of the nucleus accumbens resulted in significantly attenuated intake of palatable diet, body weight gain and fat accretion, compared with vehicle control injections. The injection of BFNA in the core did not significantly change these parameters in chow-fed control rats. The injection of BFNA in the core and shell differentially affected intake of the two palatable food items: in the core, BFNA significantly reduced the intake of high-fat, but not of Ensure, whereas in the shell, it significantly reduced the intake of Ensure, but not of high-fat, compared with vehicle treatment.. Endogenous micro-opioid receptor signaling in the nucleus accumbens core and shell is necessary for palatable diet-induced hyperphagia and obesity to fully develop in rats. Sweet and non-sweet fatty foods may be differentially processed in subcomponents of the ventral striatum.

Topics: Animals; Body Weight; Dietary Fats; Dietary Sucrose; Food Preferences; Food, Formulated; Male; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

The present study examined the interrelationships between feeding responses produced by mu opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the mu-sensitive opioid peptide, beta-endorphin (betaEND, 10 microg, i.c.v.) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01-10 nmol, i.c.v.). Moreover, the selective mu opioid antagonist, beta-funaltrexamine (betaFNA: 2-20 mug, i.c.v.), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, i.c.v.), especially at those intake periods (24-48 h) when SHU-9119 produced maximal ingestive effects. These data extend previous findings demonstrating interactions between opioid and melanocortin receptors in the mediation of food intake.

Topics: Animals; beta-Endorphin; Body Weight; Dose-Response Relationship, Drug; Eating; Male; Melanocyte-Stimulating Hormones; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Melanocortin; Receptors, Opioid, mu

The study describes a model of chronic intestinal inflammation in mice. Inflammation was induced by the administration of one dose of croton oil (CO) (acute CO) or two doses (chronic CO) of intragastric CO, whereas controls received saline (SS); GI transit was measured with charcoal. Chronic CO induced intestinal inflammation substantiated by optical microscopy, weight loss (20%) and a 25% increase in GI transit. The ED50 values in SS animals were 1.67 +/- 0.13 mg/kg for morphine and 0.038 +/- 0.006 mg/kg for fentanyl; chronic CO significantly decreased the ED50 values to 0.16 +/- 0.03 mg/kg (morphine) and 0.006 +/- 0.0005 mg/kg (fentanyl). Thus the potency of morphine increased 10.4 times and that of fentanyl 6.3 times. The effects of enkephalin, but not those of U-50488H, were also significantly enhanced during chronic CO. The antitransit effects of p.o. loperamide increased 11.7 times during chronic CO. All effects were reversed by specific antagonists. The fraction of the active opioid receptor that mediates the antitransit effects of morphine was evaluated using beta-funaltrexamine. In chronic CO, the doses of beta-funaltrexamine needed to antagonize 1 mg/kg of morphine were significantly higher than in SS and acute CO, and the ED50/KA ratio was 20 times lower. These results suggest an increase in the active concentration of mu-opioid receptors during chronic inflammation.

Topics: Animals; Antidiarrheals; Body Weight; Carbon Monoxide; Enteritis; Gastrointestinal Transit; Jejunum; Loperamide; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Receptors, Opioid

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

The present experiments were performed to investigate the effects of the selective mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on the physical dependence liability of butorphanol (a mixed agonist/antagonist opioid analgesic). Butorphanol (26 nmol/microliter/h) was continuously infused via osmotic minipumps into the lateral cerebral ventricle of male Sprague-Dawley rats for 72 h. beta-FNA (12, 24, and 48 nmol/5 microliter/rat) was administered ICV 3 h prior to and 48 h after initiation of the butorphanol infusion. Treatment with beta-FNA significantly diminished naloxone-induced escape behavior, hypothermia, and loss of body weight in a dose-dependent manner, while naloxone-induced teeth-chattering, forepaw tremors, and urination were also reduced, but in a dose-independent manner. These results suggest that the mu opioid receptor is partially involved in the development of physical dependence upon butorphanol.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Butorphanol; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Reinforcement Schedule; Substance Withdrawal Syndrome; Substance-Related Disorders

The effects of beta-FNA, a highly selective and irreversible mu opioid receptor antagonist, in altering body and brain development in preweaning rats were determined. Animals given beta-FNA did not differ from controls in body weights, brain and cerebellar weights, macroscopic dimensions of the brain, the area of the cerebellum, or in organ weight. The dosage of beta-FNA utilized (5 mg/kg) blocked morphine-induced analgesia (2 mg/kg morphine sulfate, SC) for each injection period (i.e., 48 hr). In contrast to beta-FNA treatment, rats given naltrexone (50 mg/kg SC) in a regimen which completely blocked the opioid receptor throughout ontogeny exhibited marked increases in somatic and neurobiological growth. These results suggest that, in and by themselves, mu receptors selectively antagonized by beta-FNA do not play an important role in regulating development.

Topics: Animals; Body Weight; Brain; Cerebellum; Female; Male; Morphine; Naltrexone; Nociceptors; Rats; Rats, Inbred Strains; Receptors, Opioid

The opioid mu receptor antagonist beta-funaltrexamine (beta-FNA) blocked the development of physical dependence in rats when infused simultaneously with morphine for 6 days. In addition, beta-FNA given s.c. 24 h prior to the initiation and on day 3 of a 6 day period of morphine infusion in rats reduced the development of physical dependence in a dose-dependent manner. In morphine-dependent rhesus monkeys, beta-FNA precipitated a prompt and long-lasting withdrawal, which was not reversed within 30 h by subsequent injections of morphine. In contrast, naloxone-induced withdrawal lasted approximately 90 min. These results provide further evidence that beta-FNA is a long-acting antagonist of the opioid mu receptor, and that this receptor has a major role in the development of morphine-induced physical dependence.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Macaca mulatta; Male; Morphine Dependence; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Species Specificity; Substance Withdrawal Syndrome; Time Factors

We previously demonstrated that the spinal cord is a primary site for the development of morphine-induced tolerance and dependence. In the current investigation, we have determined the significance of mu opioid receptors in the spinal cord in tolerance and dependence induced by systemically administered morphine. Rats surgically implanted with intrathecal (i.t.) catheters were injected i.t. with various doses of beta-funaltrexamine (beta-FNA), a specific irreversible mu opioid receptor antagonist. beta-FNA (i.t.) dose-dependently antagonized morphine-induced analgesia (i.p.) with approximately one-half the potency of beta-chlornaltrexamine, a nonselective irreversible opioid receptor antagonist. Rats injected with saline i.t. 24 h before implanting morphine pellets developed a significant degree of tolerance and dependence 72 h after morphine administration. Tolerance did not develop in similarly treated animals that received i.t. injections of 4.5 nmol beta-FNA. Signs of naloxone-precipitated withdrawal were also significantly antagonized in all instances, except weight loss, in animals pretreated with beta-FNA (i.t.). We conclude that i.t. injections of beta-FNA significantly antagonized the development of tolerance and dependence induced by systemically administered morphine. Therefore, our results indicate that mu opioid receptors within the spinal cord, and probably throughout the central nervous system, play a primary role in morphine-induced tolerance and dependence.

Topics: Analgesia; Animals; Body Weight; Drug Tolerance; Humans; Male; Morphine; Morphine Dependence; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu; Spinal Cord