Effects Of Β-endorphin Research Articles

In vivo and in vitro effects of beta-endorphin on glucose metabolism in the rat.

The effects of beta-endorphin (beta-Ep) on plasma glucose levels in rats and on glucose metabolism in isolated rat liver cells were examined. Intravenous injection of beta-Ep (5 micrograms/100 g BW) into ether-anaesthetized rats resulted in prompt and sustained hyperglycaemia with increases in the plasma glucagon and somatostatin levels and decrease in the plasma insulin level. When liver cells isolated from fed rats were incubated in the presence of beta-Ep at concentrations of 6 X 10(-8) M to 6 X 10(-7) M, glucose release into the medium increased within 15 min in a dose-related manner. Time course experiments showed that beta-Ep increased the level of cyclic AMP within 3 min. Significant increase in gluconeogenesis in liver cells isolated from fasted rats was also observed on addition of 10(-7) M beta-Ep in the presence of 10 mM L-lactate. These results suggest that the hyperglycaemia induced by beta-Ep may be caused, at least in part, by the effects of beta-Ep on releases of pancreatic hormones and glucose production in liver cells.

Low doses of β-endorphin increase social contacts of rats tested in dyadic encounters

Social isolation for 7 days increases the frequency of social interactions of rats, when they are tested with non-isolated partners in dyadic encounters. Subcutaneous administration of β-endorphin enhances the social interactions of the isolated animals. Especially contact behavior, which includes crawl over, mounting and social grooming is stimulated by β-endorphin, whereas social explorative behavior and approaching/following are less or not changed by peptide treatment. Already 10 ng/kg of the peptide increases the social interactions, especially social contacts of the rats. Treatment with naltrexone does not interfere with the social interactions of the isolated animals, but completely antagonizes the β-endorphin-induced increase of social behavior, suggesting that this effect of β-endorphin is mediated by opiate receptor systems. It is postulated that β-endorphin modulates close and intimate social contacts probably by its reward-inducing properties.

Effect of β-endorphin on gastric acid secretion and serum gastrin concentration in humans

The effect of synthetic human β-endorphin on gastric acid secretion was studied in 9 healthy subjects. Neither 2.5 mg or 15 mg β-endorphin had a significant effect on acid secretion or on serum gastrin concentration despite the fact that this dose of opiate caused a significant increase in serum prolactin concentrations. The role of endogenous opiate-like peptides on gastric secretion is discussed.

Cardiovascular and Respiratory Effects of β-Endorphin in Anesthetized and Conscious Rats

This study deals with the effects of beta-endorphin on blood pressure, heart rate, and respiratory frequency in anesthetized and conscious rats after both peripheral and central administration. Intravenous injection of beta-endorphin (40 and 160 micrograms/kg) in urethane-anesthetized rats resulted in a prolonged decrease in blood pressure, which, after the higher dose, was accompanied by bradycardia. In the pentobarbitone-anesthetized animals the same doses of beta-endorphin caused a small rise in blood pressure without affecting heart rate. No effect on respiratory frequency was observed. In urethane-anesthetized rats with hemorrhagic shock intravenous naloxone elicited a small pressor effect. Intracerebroventricular injection (i.c.v.) of beta-endorphin (40 micrograms/rat) in urethane-anesthetized rats resulted in severe respiratory depression and death. With lower doses there was a decrease in all parameters studied without ensuing death. Respiratory depression was even more pronounced in pentobarbitone-anesthetized rats, occurring with much lower doses of the peptide than in the urethane-anesthetized animals. beta-endorphin in the dose of 0.6 micrograms/rat still reduced respiratory frequency as well as heart rate without affecting blood pressure. Naloxone pretreatment antagonized the respiratory depression and death, while the decrease in heart rate was diminished. In conscious rats 10 microgram/rat, i.c.v., of beta-endorphin resulted in a decrease in heart rate and blood pressure without affecting respiratory frequency. It is concluded that beta-endorphin, or related opioid peptides, may be involved in cardiovascular and respiratory regulation. The effects of beta-endorphin, however, are markedly modified by the anesthetic agent used.

Selective inhibition of ‘motor endplate-specific’ acetylcholinesterase by β-endorphin and related peptides

The effects of β-endorphin (lipotropin 61–91) and related naturally-occurring peptides upon acetylcholinesterase activity in rat hind-limb muscles was investigated. β-endorphin weakly inhibited the activity in a plasma membrane-enriched fraction. The inhibition by β-endorphin of the membrane-associated acetylcholinesterase was less marked when the fractions were prepared from muscles which had been denervated 4–6 days previously. The membrane-associated acetylcholinesterase was solubilised from normal muscle preparations and separated by sucrose density gradient centrifugation into three major peaks (16S, 10S and 4S). β-Endorphin inhibited the activity in the 16S peak but not that in the 10S and 4S peaks, whilst tensilon, a competitive inhibitor of acetylcholinesterase, inhibited the activity of all three peaks. β-Endorphin inhibited the 16S activity in a concentration-dependent manner and its action was partly prevented if naloxone was added simultaneously. Purified natural porcine and bovine β-endorphin were equipotent in terms of effective concentration range but the maximum inhibition was greater with the bovine peptide. β-Lipotropin was approximately 4 times less potent than β-endorphin, whilst C'-fragment (lipotropin 61–87) was 100 times less potent. Prolonged treatment with collagenase did not reduce the catalytic activity of 16S acetylcholinesterase, but it was no longer susceptible to the inhibitory action of β-endorphin. Kinetic studies indicated a complex type of inhibition by β-endorphin (hyperbolic Lineweaver-Burke plot). Methionine enkephalin inhibited acetylcholinesterase in a weakly non-competitive manner and its action was not abolished if the enzyme was predigested with collagenase. β-Endorphin produces a novel form of inhibition of acetylcholinesterase, acting only on the 16S (A12 or ‘motor endplate-specific’) form of the enzyme. The findings are discussed in the light of evidence that β-endorphin-related immunoreactivity is expressed in motor nerve axons in the immature rat.

Modification of d-amphetamine- or chlorpromazine-induced hypothermia by β-endorphin, MIF-I, and α-MSH: Mediation by the dopaminergic system

The effects of β-endorphin, MIF-I, and α-MSH on d-amphetamine- and CPZ-induced hypothermias in rats kept at 4°C were tested in three experimental groups: (a) intact; (b) rats with lesions of the olfactory tubercle; and (c) rats in which the link between the DA mesolimbic pathway and the striatum was disconnected. All drugs tested alone (except MIF-I) caused significant hypothermia. Pretreatment with CPZ, MIF-I, and α-MSH potentiated d-amphetamine-induced hypothermia in intact rats. Pretreatment with α-MSH potentiated CPZ-induced hypothermia. β-Endorphin partially blocked d-amphetamine-induced hypothermia, but did not interact with CPZ, MIF-I, or α-MSH. All potentiations were either reduced or disappeared in the incisioned rats. CPZ and α-MSH caused hypothermia in olfactory tubercle-lesioned rats. The results indicate that: (a) the DA mesolimbic pathway is involved in the hypothermic response of all drugs tested; (b) an intact feedback loop is required for the potentiation of the hypothermic response of CPZ on d-amphetamine, MIF-I on d-amphetamine, and α-MSH on d-amphetamine and CPZ; (c) β-endorphin acts as a partial blocker of d-amphetamine; MIF-I is a weak potentiator of d-amphetamine. α-MSH acts as a negative modulator of the DA system, most probably in the striatum.

Modulation of spontaneous seizures in the Mongolian gerbil: Effects of β-endorphin

Intraventricular injection of β-endorphin (0.1–3 μg) into gerbils from the UCLA seizure sensitive strain reduced the incidence and severity of spontaneous epileptiform seizures, both the motor manifestations and the preceding high voltage focal spiking and accompanying seizure activity in the cortical EEG. This “anticonvulsant” effect of β-endorphin was prevented by prior administration of naloxone (1 mg·kg −1 IP). These findings suggest that the endogenous opioid peptide may be involved in the normal suppression of the epileptic diathesis in these animals during the interictal periods.

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.

Excitability to β-endorphin, morphine and catecholamines of the vas deferens of the rat at different stages of development

The effect of β-endorphin and morphine on neuromuscular twitching of the vas deferens was examined in rats of 10–120 days of age. The maximal tension developed by the smooth muscle was markedly dependent on the age of the rat and on the kind of stimulus applied. The potency of β-endorphin to inhibit the electrically induced twitching or of catecholamines to induce muscle contraction was not significantly altered by development of the animal. The excitatory action of morphine showed significant variations in activity reaching maximal sensitivity at about two months of age. Age or the onset of puberty do not significantly modify the sensitivity of the vas deferens to β-endorphin; the peptide may play the role of modulating adrenergic transmission.

Inhibition by β-endorphin of isoprenaline-induced vasopressin release and its reversal by naloxone

The effect of β-endorphin on isoprenaline-induced vasopressin release was investigated in rats. β-Endorphin (0.29 nmol i.c.v. or 2.9 nmol i.v.) suppressed markedly the increase in plasma vasopressin concentrations in response to isoprenaline without altering the concomitant increase in plasma renin concentration or fall in mean arterial blood pressure. Naloxone (1 mg/kg) prevented this inhibition as did chronic morphine pretreatment. These results show that β-endorphin can inhibit isoprenaline-induced vasopressin release by acting on opiate receptors.

Effects of beta-endorphin and morphine on the sleep-wakefulness behavior of cats.

The effects of beta-endorphin and of morphine SO4 (0.5 microgram and 2.0 microgram, respectively, injected intraventricularly) upon the sleep-wakefulness behavior of cats were examined. Both agents produced insomnia. Deep slow wave sleep was sharply inhibited, and rapid eye movement (REM) sleep was entirely suppressed. Light slow wave sleep, occurring in brief, isolated episodes, became the most abundant stage of sleep. The nuchal electromyogram was markedly increased after both agents. Naloxone (100 microgram/kg), injected subcutaneously 30 min before beta-endorphin or morphine SO4, entirely reversed these agents' effects on the two stages of slow wave sleep, and antagonized the exaggerated electromyogram. But naloxone did not counteract the REM-suppressant effect of either beta-endorphin or morphine SO4. Total sleep time reverted towards control values after naloxone pretreatment, but not entirely; the difference may be due to the persistent deficit of REM sleep. The data may indicate an involvement of an inner opioid in the regulation of sleep and wakefulness in the cat, and may point to a role for more than one endorphin receptor in the effects of opioids on the states of vigilance in cats.

Effects of β-endorphin, met-enkephalin and somatostatin on the neurotensin-induced neurogenic contraction in the guinea-pig ileum

At maximally effective concentrations, the opiate peptides β-endorphin (240 nm) and Met-enkephalin (1400 nM) virtually abolished the contractions induced by a maximally effective concentration of 60 nM neurotensin (NT), either in the longitudinal smooth muscle strip or in the intact segment of guinea-pig ileum. This inhibitory effect was concentration-dependent and was totally blocked by naloxone at 100 nM. In contrast a maximally effective concentration of somatostatin (60 nM) partially inhibited (50–60%) the contraction induced by 60 nM NT in either smooth muscle preparation. Somatostatin inhibition was concentration-dependent and was not blocked by naloxone at 100 nM. Atropine at 100 nM inhibited by 50% the contractions induced by 60 nM NT in the intact segment of guinea-pig ileum. The remaining contraction was abolished by β-endorphin and Met-enkephalin and partially reduced by somatostatin. Our results confirm that NT-induced contractions in the guinea-pig ileum are neurogenic and involve a cholinergic as well as a non-cholinergic component. Furthermore, we show that the release of mediators from both components

Reduction by β-endorphin of efflux of dopamine and dopac from superfused medial basal hypothalamus

The effects of β-endorphin (β-EP) and naloxone on the efflux of dopamine (DA) and its specific deaminated metabolite, dihydroxyphenylacetic acid (DOPAC), from superfused rat medial basal hypothalamus (MBH) were determined. After an equilibration period of 2.5 hrs with Medium 199 at 37°C 0.5 ml fractions were collected. Injection of β-EP, but not medium, into the system significantly reduced (P<0.05) the effluent concentrations of both DA and DOPAC from female MBH's (N=5) by 71% and 55% respectively and from male MBH's (N=7) by 68% and 49% respectively. Conversely, administration of naloxone significantly increased DA and DOPAC efflux by 85% and 148% respectively in females and by 132% and 120% in males. When an equimolar mixture of β-EP and naloxone was injected, no detectable changes in DA and DOPAC efflux were found. The effects of β-EP and naloxone were demonstrable irrespective of the sequence of administration. We conclude that β-EP exerts a tonic inhibitory effect on tuberoinfundibular DA neurons by interaction with naloxone-sensitive opiate receptors. This action does not require the intermediation of brain centers outside the MBH.

Hormone ontogeny in the ovine fetus. X. The effects of beta-endorphin and naloxone on circulating growth hormone, prolactin, and chorionic somatomammotropin.

The potential role of beta-endorphin (beta-EP) as a stimulus to fetal GH, PRL, and chorionic somatomammotropin secretion was investigated in the chronically catheterized ovine fetus. beta-EP (500 microgram/kg, iv) was administered to six fetuses between 84-100 days gestation and to four fetuses between 112-131 days gestation (term, 147 days). The peak incremental GH response of 104.4 +/- 21.1 ng/ml in the younger fetuses was greater (P less than 0.01) than that of the older fetuses (38.0 +/- 11.9 ng/ml). Pretreatment of the fetus with naloxone (100-500 microgram/kg, iv) 5 min before beta-EP reduced (P less than 0.02) the GH response to beta-EP, which suggests that the GH stimulating action of beta-EP was mediated via opiate receptors. Naloxone alone (400 microgram/kg, iv bolus, followed by 400 microgram/kg over 1 h of infusion) had no significant effect on fetal plasma GH. There was no significant change in plasma PRL after beta-EP; however, fetal PRL rose in the three oldest fetuses studied (122, 126, and 131 days). Fetal ovine chorionic somatomammotropin was not altered by either beta-EP or naloxone. The fetal hypothalamic pituitary unit can respond by mid-gestation to exogenous beta-EP with increasing GH secretion. However, in late gestation, the GH responsiveness to beta-EP decreases significantly. It is postulated that this decreased responsiveness is a consequence of the maturation of hypothalamic inhibitory mechanisms regulating GH secretion. The effects of beta-EP on GH and PRL secretion are dissociated in the ovine fetus.

Beta-Endorphin-induced prolactin secretion is mediated by suppression of release of newly synthesized hypothalamic dopamine.

Intracisternal administration of synthetic human β-endorphin in rats increased plasma prolactin. This effect of β-endorphin is blocked completely by parenteral administration of the dopamine receptor agonist, apomorphine. Increasing availability of brain dopamine with the monoamine oxidase inhibitor, pargyline, blunted the effect of β-endorphin on plasma prolactin. Although the effect of apomorphine could have been mediated either in the hypothalamus or directly on pituitary, the action of pargyline could not have occurred in pituitary, thus providing support for the hypothesis that β-endorphin-induced prolactin secretion is mediated in brain and furthermore through a dopaminergic mechanism. Additional support for both aspects of this hypothesis is provided by the finding that decreasing availability of dopamine with the dopamine synthesis inhibitor, α-methyltyrosine, potentiated the effect of β-endorphin to increase plasma prolactin concentration.Furthermore, this potentiation by α-methyltyrosine of β-endorphin-induced prolactin secretion was evident at a time when mediobasal hypothalamic dopamine concentration had not yet decreased. Because the storage pool of dopamine does not appear to have been altered at this time, these data suggest that lack of newly synthesized hypothalamic dopamine potentiated the effect of β-endorphin to increase plasma prolactin. It seems probable that inhibition of release of newly synthesized (and preferentially released) tuberoinfundibular dopamine is important in mediating β-endorphin-induced prolactin secretion. Finally, intracisternal dexamethasone inhibited the synergistic effects of α-methyltyrosine and β-endorphin on prolactin secretion, perhaps by an action on hypothalamic aminergic neurons.

Effects of β-endorphin, Met-enkephalin and somatostatin on the neurotensin-induced neurogenic contraction in the guinea-pig ileum

Effects of β-endorphin, Met-enkephalin and somatostatin on the neurotensin-induced neurogenic contraction in the guinea-pig ileum

Effect of β-Endorphin on Calcium Uptake in the Brain

The uptake of 45Ca2+ by nerve-ending fractions from brains of mice was inhibited in vitro by 10(-9)M concentrations of beta-endorphin and in mice injected intraventricularly with 7 picomoles of beta-endorphin. That the effect was a specific opiate agonist response of beta-endorphin was demonstrated by use of the opiate antagonist, naloxone, which reversed the action. A role for beta-endorphin in the regulation of calcium flux and neurotransmitter release should be considered.

β-endorphin is a kidney trophic hormone

Intravenous injection of the opioid peptide β-endorphin stimulated an increase in the activity of renal ornithine decarboxylase in rats. The induction of this enzyme is a marker of the growth response of trophic hormone target tissues. Morphine administration promoted an even greater increase in the enzyme activity, which was blocked by the simultaneous administration of the specific opiate antagonist, naloxone. Although hypophysectomy lowered the basal level of ornithine decarboxylase in the kidney, the trophic response to either opioid administration remained intact. This effect of β-endorphin on the kidney may represent a functional role for the circulating endogenous opioid.

Effects of β-endorphin and D-alanine 2 enkephalinamide on urine production and urinary electrolytes in the rat

The intracerebro-ventricular administration of human β-Endorphin (β-EP, 0.1–3 μg/rat) or D-alanine 2 methionine enkephalinamide (D-ala, 0.3–30 μg/rat) caused a dose dependent reduction in the urine volume. The oliguria was associated with a decrease in the concentration of Na + and K + in the urine of rats previously hydrated by oral administration with 25 ml/kg tap water plus 50 ml/kg 0.5% NaCl. On a molar basis, β-EP proved to be about 5–7 times more potent than D-ala. The effects caused by the peptides were antagonized by the simultaneous intraperitoneal administration of 1 mg/kg naloxone. In rats treated chronically with morphine, no cross-tolerance was demonstrated to the antidiuretic effect of β-EP, but clear cross-tolerance was evident to the changes in urine electrolytes induced by β-EP. Results suggest that morphine and the opiate peptides share a similar mechanism of action.

Effects of β-endorphin on brain serotonin metabolism

Human β-endorphin (15 μg) administered intracisternally increased concentrations of serotonin (5HT) and its metabolite, 5-hydroxyindoleacetic. acid (5-HIAA), in brain stem and hypothalamus and decreased 5-HIAA concentrations in hippocampus. These data are compatible with the hypothesis that β-endorphin increases 5HT turnover in brain stem and hypothalamus and decreases 5HT turnover in hippocampus. β-endorphin increased in brain stem and hypothalamus and decreased in hippocampus the rate of pargyline-induced decline of 5-HIAA. β-endorphin decreased the rate of pargyline-induced accumulation of 5HT in all these brain regions. The probenecid-induced accumulation of 5-HIAA in brain stem was decreased by β-endorphin. These data are compatible with the hypothesis that β-endorphin increases release of 5HT from neurons in brain stem and hypothalamus and decreases release of 5HT from neurons in hippocampus. The data require further a hypothesis that β-endorphin either decreases 5HT reuptake in these three brain regions or increases 5-HIAA egress from brain.