β-endorphin: Effects on respiratory regulation

Intracisternal injection of 14.5 nmoles of human β-endorphin in lightly anesthetized dogs resulted in marked respiratory depression, manifested by diminished responses of ventilation and airway occlusion pressure to carbon dioxide rebreathing. These responses were temporarily reversed by intravenous injection of naloxone and attenuated following a second β-endorphin injection. Results in this study suggest a possible physiological role for endogenous opioid peptides in the regulation of respiration.     

Naltrexone reduces weight gain, alters “β-endorphin”, and reduces insulin output from pancreatic islets of genetically obese mice

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 β-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 β-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 β-endorphins rose 4–6 fold in ob/ob compared with +/?. While naltrexone reduced the levels in ob/ob pituitary towards normal, no effect on β-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.     

Beta-endorphin induced akinesia in rats: effect of apomorhine and alpha-methyl-p-tyrosine and related modifications of dopamine turnover in the basal ganglia

β-Endorphin (amino acid sequence 61–91 of β-lipotropin) administered intraventricularly at a dose of 13 n moles in rat induced akinesia and loss of corneal reflex. Apomorphine (20 mg/kg) which had been injected subcutaneously 20 minutes after the administration of β-endorphin fully reversed akinesia and elicited characteristic stereotyped behavior. During complete disappearance of akinesia, the corneal reflex was found to be still absent. Apomorphine (5 mg/kg) only partially reversed akinesia. Pretreatment with α-methyl-p-tyrosine (α-MT, 250 mg/kg) potentiated the effect of β-endorphin upon muscle rigidity. In a biochemical study, rats received β-endorphin (15 n moles) 60 minutes before sacrifice. Concentrations of dopamine (DA) and norepinephrine (NE) were not altered in any brain regions. A significant increase in concentrations of 5-hydroxytryptamine was obtained in the midbrain. In a DA and NE turnover study, rats received α-MT (250 mg/kg) 4 hours prior to β-endorphin and were sacrificed 60 minutes later. β-Endorphin partially corrected the decreased concentrations of DA induced by α-MT in the midbrain. A similar tendency toward correction of the decreased DA concentrations was observed in the striatum. The concentrations of NE decreased by α-MT in the midbrain, striatum and hypothalamus were not modified by β-endorphin     

Endorphins and the central inhibition of urinary bladder motility

The involvement of endogenous opioid mechanisms in the central neurogenic control of urinary bladder function has been examined in anesthetized rats. Intracerebroventricular (ICV) microinjection of β-endorphin (0.5–2.0 μg) produced powerful inhibition of rhythmic bladder contractions initiated by central reflex activity. The peptide fragments γ-endorphin and α-endorphin (4–16 μg), formed by the processing of β-endorphin by membrane homogenates of brain, were less active than the parent compound. The inhibitory effects of β-endorphin was reversed by ICV naloxone (1–2 μg) but higher doses were required to reverse γ- or α-endorphin effects. ICV naloxone administered alone increased intravesicular pressure and bladder contraction frequency. These observations support the hypothesis that the endorphins have a physiological role in the central regulation of urinary bladder activity.     

Comparison of analgesic and body temperature responses to intrathecal beta-endorphin and D-Ala2-D-Leu5-enkephalin

The inhibition of tail flick response to radiant heat and body temperature changes after intrathecal administration of β-endorphin (β-EP) and D-Ala²-D-Leu⁵-enkephalin (DADL) were studied in rats. Both opioid peptides caused inhibition of tail flick response. On a molar basis, β-EP was 73% as potent as DADL, but the duration of tail flick inhibition of β-EP was much longer than that of DADL. β-EP induced hyperthermia while DADL did not cause any significant change in body temperature. The tail flick inhibition induced by β-EP (1 nmole) was reversed by 2 mg/kg of naloxone, ip; however, the tail flick inhibition induced by DADL (7 nmole) was not reversed by 2 mg/kg and was incompletely reversed by a higher dose of naloxone one (6 mg/kg, ip). These studies demonstrate the existence of naloxone-resistant opioid receptors in the spinal cord which are sensitive to enkephalin. These results indicate that the opioid receptors involved in the production of opioid responses in the spinal cord are different from those in supraspinal brain areas.     

Effect of excitotoxic lesions of the neonatal ventral hippocampus on the immobility response in rats

Rats with neonatal ventral hippocampal (nVH) lesions show postpubertal hypersensitivity to dopamine agonists, which may be reversed by neuroleptic treatment. In addition, the immobility response (IR) may be regulated by dopaminergic activity. We investigated the influence of the IR caused by clamping the neck of rats that had received bilateral ibotenic acid lesions of the ventral hippocampus at postnatal day 7 (PD7). At both ages, prepubertal (PD35) and postpubertal (PD56), the duration of the IR was significantly increased in animals with lesions when compared to controls. These findings indicate that nVH damage results in behavioral changes, such as enhancement of the IR, related to mesolimbic dopaminergic transmission.     

Effects of 2-bromo-α-ergocryptine on β-endorphin-induced growth hormone,prolactin and luteining hormone release in urethane anesthetized rats

Adult male rats were injected intraperitoneally either with saline or 2-Br- α-ergocryptine(CB-154)(10 ng/0.5 ml/rat) 30 min prior to an intraventricular injection of saline or β-endorphin (1 μg/10 μl or 5 μg/10 μl) and 30 min after β-endorphin, they were sacrificed by decapitation. Intraventricular injection of β-endorphin elicited significant increases in serum GH, prolactin and LH levels in a dose-related manner. Pretreatment with CB-154 inhibited the release of GH, prolactin and LH induced by β-endorphin. These results indicate that the stimulatory effects of β-endorphin on GH, prolactin and LH may be involved in an inhibition of dopaminergic mechanism in the central nervous system.     

Pituitary responsiveness to luteinizing hormone-releasing hormone in prepubertal and postpubertal male ferrets

The pituitary response to three different doses of exogenously administered LHRH was examined in prepubertal (9-wk-old) and postpubertal (32-wk-old) male ferrets. The doses of 5, 10, and 15 ng LHRH/kg body weight tested in this study produced dose-related increases in circulating LH concentrations in both pre- and postpubertal groups. In addition, a significant effect of age on LH response was observed, with the prepubertal animals demonstrating significantly greater serum LH values in response to the two higher doses than the postpubertal males. Prepubertal ferrets also exhibited a significant increase in endogenous LH pulse amplitude in sampling periods following exogenous administration of LHRH compared to baseline pulse amplitudes in periods prior to the LHRH infusions. These results suggest that the low frequency of endogenous LH pulses previously observed in prepubertal ferrets is not due to unresponsiveness of the pituitary gland to LHRH. Thus, suppression of the hypothalamo-hypophyseal axis observed in the prepubertal ferret is probably mediated at the level of the hypothalamus.     

Pituitary β-endorphin content during spontaneous food intake and body weight cycles in the dormouse, Glis glis

Pituitary β-endorphin content was measured in dormice during several distinct phases of the infradian body weight cycle. No significant differences in opiate content among groups were found. It appears unlikely that pituitary concentrations of β-endorphin have etiological significance in the development of spontaneous obesity in hibernators.     

Comparison of opiate- and opioid-peptide-induced immobility.

Intraventricular administration of the endogenous opioid peptide β-endorphin produces a profound state of immobilization in rats characterized by the absence of spontaneous movement, loss of the righting response and extreme generalized muscular rigidity. The immobility syndrome induced by the opioid peptides β-endorphin and D-Met²-Pro⁵-enkephalinamide was compared with the behavioral profile prodced by subcutaneous and intraventricular administration of the opiates, morphine, methadone and etonitazene. The results indicate a close similarity between the pattern of effects caused by the opiates and opioid peptides. The immobility syndrome could also be produced by injection of β-endorphin into the ventromedial periaqueductal gray, but not into the caudate, globus pallidus, amygdala or dorsolateral periaqueductal gray. The resemblance between the opiate- and β-endorphin-induced profiles suggests that their effects are mediated through common mechanisms.     

Sex Differences in the Content of β-Endorphin and Enkephalin-Like Peptides in the Pituitary of Obese (ob/ob) Mice

Abstract: The β-endorphin content in pituitary extracts of male and female obese (ob/ob) and lean (+/?) mice was determined by radioimmunoassay. The amount of β-endorphin-like material contained in the pituitary of 3-month-old ob/ob male mice is similar to that of lean male mice. In contrast, the pituitary glands of female ob/ob mice have a greater amount of β-endorphin-like material than lean female mice. To determine with greater precision the molecular nature of the polypeptide that accounts for the increase in β-endorphin immunoreactivity, the various molecular forms of β-endorphin immunoreactivity were resolved by Biogel P-30 column chromatography. At least four peaks of immunoreactive material were detected. The first peak elutes in the void volume, and the second and the third peaks appear in the elution volumes of β-lipotropin and β-endorphin, respectively. That the material present in the void volume might be proopiocortin is supported by adrenocorticotropic hormone radioimmunoassay. The increased total β-endorphin immunoreactivity in pituitary glands of ob/ob mice is accounted for mainly by β-endorphin. The β-endorphin content of various brain structures of ob/ob mice is similar to that of lean littermates.     

Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism. Research Methods and Procedures: Chronically, olanzapine or clozapine was self‐administered via cookie dough to rodents (Sprague‐Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ～24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion: A model of olanzapine‐induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug‐induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine‐induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.     

Comparison of the behavioral effects of β-endorphin and enkephalin analogs

The behavioral effects of β-endorphin, enkephalin analogs, morphine and etorphine were briefly compared. In the tail-flick test in mice and in the wet shake test in rats, β-endorphin and D-Ala²-D-Leu⁵-enkephalin had equal antinociceptive activity; D-Ala² -Met-enkephalinamide and D-Leu⁵-enkephalin were less active. The order of activity of the enkephalin analogs and opiate alkaloids for stimulating locomotor activity in mice paralleled their analgesic activities; β-endorphin, however, had only minimal stimulatory actions. Morphine sulfate, 50 μg injected into the periaqueductal gray, produced hyperactivity but this effect was not observed with etorphine or opioid peptides. By contrast, “wet dog” shakes was observed with the opioid peptides but not with either opiate alkaloid. These heterogenous behavioral responses, which were all antagonized by naloxone, indicate that multiple types of receptors mediate the effects of opiates in the central nervous system.     

The effect of β-endorphin on arginine-induced growth hormone and prolactin release

β-endorphin administration via constant infusion inhibited the release of growth hormone (GH) and augmented the release of prolactin (PRL) induced by arginine in normal female subjects. Although β-endorphin infusion also induced hyperglycemia, the increment in plasma glucose was insufficient to account for the observed suppression of arginine-initiated GH release. These studies demonstrate that β-endorphin influences, in opposed directions, the secretion of PRL and GH in women.     

β-Endorphinergic system involvement in the inhibitory action of clonidine on induced sodium appetite

In the present study, we investigated the degree to which β-endorphin plays a role in the alpha 2-adrenergic/imidazoline receptor agonist attenuation of salt appetite. In order to evaluate whether the inhibitory action of clonidine (an α2-adrenergic/imidazoline receptor agonist) on induced sodium intake is mediated by the β-endorphinergic system, we used a β-endorphin deficient mouse line. β-endorphin knockout (βend(-/-)), heterozygous (βend(+/-)) and wild-type (βend(+/+)) mice were submitted to acute sodium depletion by a combined treatment of furosemide and low sodium diet and, 20h later, were administered with clonidine (0.5mg/kg). An hour later, the animals were subjected to a two-bottle choice test (water/2% NaCl). The results indicate that clonidine administration during the first stage of the test exerts an equivalent inhibition on sodium intake regardless of the genotype; however, in the final stage of the test, a reversal of the inhibitory response on induced sodium appetite becomes evident in the mice lacking β-endorphin. Moreover no differences in dipsogenic response were observed between the genotypes. Considering these results and the fact that plasma half-life of clonidine at the dose administered is approximately 3h, it is possible to speculate that the inhibitory effect of clonidine on sodium appetite may be independent of β-endorphin modulation during the first stage; however, the long-lasting inhibitory effect of clonidine may be mediated by the β-endorphinergic system. This evidence supports the existence of adrenergic and β-endorphinergic system interaction in the osmoregulatory response to achieve sodium balance.     

Prolonged fasting induces long-lasting metabolic consequences in mice

To endure prolonged fasting, animals undergo important acute physiological adjustments. However, whether severe fasting also leads to long-term metabolic adaptations is largely unknown. Forty-eight-hour fasting caused a pronounced weight loss in adult C57BL/6 male mice. Seven days of refeeding increased body adiposity to levels above baseline, whereas fasting-induced reductions in lean body mass and energy expenditure were not fully recovered. Respiratory exchange ratio and locomotor activity also remained altered. A fasting/refeeding cycle led to persistent suppression of Pomc mRNA levels and significant changes in the expression of histone deacetylases and DNA methyltransferases in the hypothalamus. Additionally, histone acetylation in the ventromedial nucleus of the hypothalamus was reduced by prolonged fasting and remained suppressed after refeeding. Mice subjected to 48-h fasting 30 days earlier exhibited higher body weight and fat mass compared to aged-matched animals that were never food-deprived. Furthermore, a previous fasting experience altered the changes in body weight, lean mass, energy expenditure and locomotor activity induced by a second cycle of fasting and refeeding. Notably, when acutely exposed to high-palatable/high-fat diet, mice that went through cumulative fasting episodes presented higher calorie intake and reduced energy expenditure and fat oxidation, compared to mice that had never been subjected to fasting. When chronically exposed to high-fat diet, mice that experienced cumulative fasting episodes showed higher gain of body and fat mass and reduced energy expenditure and calorie intake. In summary, cumulative episodes of prolonged fasting lead to hypothalamic epigenetic changes and long-lasting metabolic adaptations in mice.     

Absence of functional and structural homology of natural and recombinant human leukocyte interferon (IFN-α) with human α-ACTH and β-endorphin

A comparison of the amino acid sequence of one human recombinant IFN-α (IFLrA) with either human β-endorphin or ACTH reveals only a minimal and insignificant degree of homology. Also, synthetic ACTH, β-endorphin and β-endorphin-(1–15) have no antiviral protective effects on human fibroblasts and cannot inhibit the neutralization of the antiviral effects of natural IFN-α by an antiserum directed against the interferon. Anti ACTH and Anti β-endorphin do not neutralize the antiviral effects of IFLrA, and radioimmunoassays of partially purified natural IFN-α and pure IFLrA do not reveal any evidence of α-MSH or β-endorphin-like material in the interferons. These results demonstrate an absence of functional and structural homology of natural and recombinant IFN-α with ACTH and β-endorphin.     

Effect of myostatin depletion on weight gain, hyperglycemia, and hepatic steatosis during five months of high-fat feeding in mice

The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ～30%. Hypermuscular mice had ～50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet.     

Weight cycling and 6-year weight change in healthy adults: The Aerobics Center Longitudinal Study

Objective: To determine the longitudinal relationship between a reported history of weight cycling and the trajectory of weight in a group of normal‐weight to obese women and men. Research Methods and Procedures: This was a clinic‐based cohort study conducted over 6 years. Subjects were healthy women (n = 141) and men (n = 797) age 20 to 78 years who completed at least four comprehensive medical exams at the Cooper Clinic (Dallas, TX) between 1987 and 2003. Weight loss history was reported, and body weight was measured at all examinations. Weight cycling status was derived from weight loss history and defined as ≥five episodes of weight loss of ≥2.3 kg/episode. Using linear mixed effects models, weight at each examination was regressed on weight cycling status separately for women and men while controlling for selected covariables. Results: Baseline BMI was 23 and 21 kg/m² among cycling and non‐cycling women and was 27 and 25 kg/m² among cycling and non‐cycling men, respectively. We observed a non‐significant difference (p = 0.09) in women by cycling status (average weight gain = 0.5 and 0.2 kg/yr among cyclers and non‐cyclers, respectively) and no difference in weight gain over time among men by cycling status (average weight gain = 0.2 kg/yr among both groups, p = 0.99). Higher baseline cardiorespiratory fitness level and increased fitness over the follow‐up were associated with attenuated weight gain in both women and men. Discussion: In healthy, middle‐aged individuals, a history of weight cycling does not seem to increase the risk of long‐term weight gain in men; however, this relation needs to be studied further in women.     

Cutting edge: fasting-induced hypoleptinemia expands functional regulatory T cells in systemic lupus erythematosus

Fasting is beneficial in the prevention and amelioration of the clinical manifestations of autoimmune diseases including systemic lupus erythematosus. The mechanisms responsible for these effects are not well understood. During fasting, there is a dramatic reduction of the levels of circulating leptin, an adipokine with proinflammatory effects. Leptin also inhibits CD4(+)CD25(+)Foxp3(+) regulatory T cells, which are known to contribute significantly to the mechanisms of peripheral immune tolerance. In this study, we show that fasting-induced hypoleptinemia in (NZB × NZW)F(1) lupus-prone mice induced an expansion of functional regulatory T cells that was reversed by leptin replacement. The specificity of the findings was indicated by the lack of these effects in leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice. These observations help to explain the beneficial effects of fasting in autoimmunity and could be exploited for leptin-based immune intervention in systemic lupus erythematosus.