Beta-endorphin Secretion Research Articles

Intracerebroventricular Injection of Platelet-Activating Factor Induces Secretion of Adrenocorticotropin, Beta-Endorphin and Corticosterone in Conscious Rats: A Possible Link between the Immune and Nervous Systems

To investigate whether platelet-activating factor (PAF) exerts an indirect action on immune cells by altering the secretion of hypothalamic-pituitary-adrenal (HPA) axis products, the effects of intracerebroventricular (i.c.v.) PAF on adrenocorticotropic hormone (ACTH), beta-endorphin and corticosterone blood levels were examined in adult male rats. Hormones were radioimmunoassayed on blood samples from conscious or ether-anesthetized rats after i.c.v. injection of PAF or vehicle into the left lateral ventricle. PAF induced significant increases in these stress-related hormones under both, basal and ether-induced stress conditions. The analysis of the time course response to PAF of hormone release into the blood of unrestrained rats revealed that: i.c.v. injection of 5.4 nmol PAF resulted in rapid increases in ACTH and beta-endorphin, at the latest within 15 min after the onset of injection. The maximal response of both hormones was reached within 45 min after the onset of injection and was followed by an elevation of plasma corticosterone. Hormone release is related to the PAF dose infused, the lowest effective PAF concentration was 1 nmol. The stimulatory effect of PAF on ACTH and beta-endorphin secretion was strongly decreased in rats previously treated with purified anti-rat corticotropin-releasing factor (CRF) antibody. These results, associated with the in vitro demonstration that PAF increases CRF release from incubated rat median eminence, strongly support the hypothesis that the stimulatory action of PAF on the secretion of HPA axis products is mediated at least partly, by stimulating hypothalamic CRF release.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of Pituitary β-Endorphin by ACTH and Glucocorticoids

beta-Endorphin and ACTH are secreted concomitantly in baseline conditions and in response to physiological and pharmacological stimuli. However, few and contradictory data are available on their feedback inhibition mechanisms. To investigate this aspect, the effects of exogenous ACTH1-24 and glucocorticoids on endogenous ACTH1-39 and beta-endorphin were tested in 18 patients with Addison's disease. Two main experimental protocols were employed: (1) 7 patients were given ACTH1-24 50 micrograms as an intravenous bolus followed by a 50-micrograms infusion in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were obtained at 0, 15, 30, 45, 60, 90, 120 min. Six other patients were given oCRH 100 micrograms i.v. plus ACTH1-24, as described above. (2) In 5 other patients, hydrocortisone 37.5 mg was administered i.v. in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were drawn at 0, 15, 30, 45, 60, 90, 120 min. One week later, the same patients were given oCRH 100 micrograms i.v. and hydrocortisone 37.5 mg, as described above. ACTH1-24 administration caused a significant (p less than 0.01) decrease in endogenous ACTH but not in beta-endorphin. oCRH injection significantly stimulated both ACTH and beta-endorphin. The response of both ACTH and beta-endorphin was inhibited by exogenous ACTH1-24. There was a potent inhibition by hydrocortisone on both basal and stimulated beta-endorphin, confirming that the feedback mechanism of glucocorticoids concomitantly inhibits ACTH and beta-endorphin. On the other hand, only CRH-stimulated but not basal secretion of beta-endorphin seems affected by ACTH ultrashort feedback, suggesting an intrapituitary regulation.

Effects of Protein Kinase C Down‐Regulation on Secretory Events and Proopiomelanocortin Gene Expression in Anterior Pituitary Tumor (AtT‐20) Cells

To elucidate the role of the diacylglycerol-protein kinase C (PKC) pathway in beta-endorphin synthesis and secretion in anterior pituitary corticotrope tumor cells (AtT-20), a procedure for down-regulating PKC activity in the cells was developed. Treatment of AtT-20 cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) led to an increase in [3H]phorbol 12,13-dibutyrate binding to PKC in the membrane fraction of these cells 30 s after its addition to the culture medium. Thereafter, a decrease in both [3H]phorbol 12,13-dibutyrate binding and PKC-specific phosphotransferase activity occurred in a time- and dose-dependent manner in both the cytosolic and membrane fractions. For example, treatment of the cells with 100 nM TPA for 24 h resulted in an almost complete depletion of PKC activity. Immunoreactive beta-endorphin secretion was found to be stimulated two- to fourfold in the control cells after incubation with corticotropin-releasing factor (10(-7) M), forskolin (10(-6) M), or TPA (10(-7) M) for 4 h. In cells rendered PKC deficient, TPA-stimulated immunoreactive beta-endorphin release was abolished, forskolin-stimulated release was unaffected, and corticotropin-releasing factor-stimulated release was depressed. Treatment of control cells with any one of the three stimulatory agents led to an increase in proopiomelanocortin mRNA levels, and these responses were also depressed after TPA pretreatment. The results suggest that physiological processes thought to be entirely cyclic AMP dependent, such as corticotropin-releasing factor-elicited secretion, may be partially dependent on PKC-mediated biochemical events.

Altered pituitary hormone response to naloxone in hypertension development.

Endogenous opioid regulation of blood pressure is altered during stress in young adults at risk for hypertension. We studied the effects of the opioid antagonist naloxone on the secretion of corticotropin and beta-endorphin during psychological stress in young adults with mildly elevated casual arterial pressures. Naloxone-induced secretion of both corticotropin and beta-endorphin was significantly diminished in persons at enhanced risk for hypertension compared with the low blood pressure control group. Results suggest that opioidergic inhibition of anterior pituitary function is altered in hypertension development.

Rate-Sensitive Glucocorticoid Feedback Inhibition of Adrenocorticotropin and β-Endorphin/β-Lipotropin Secretion in Rats*

In the present study, we present physiological evidence for rate-sensitive, fast feedback inhibition of secretion of ACTH and beta-endorphin (beta END)-related peptides. We used a 2 min restraint stress to physiologically increase plasma corticosterone, then examined the plasma responses of immunoreactive ACTH and beta END plus beta-lipotropin (beta END/beta LPH) to a subsequent restraint stress. After onset of this stress, plasma corticosterone increased from 2.5-10 min at a rate of 120 nM min-1, then remained at a peak from 10-15 min. A single 2 min restraint stress produced peak plasma levels of ACTH and beta END/beta LPH 2.5 min after onset of the stress, and these plasma concentrations declined after this initial stress at rates of 2.7 and 7.4 pM min-1, respectively. Application of a second restraint stress at the time of the peak corticosterone response produced plasma ACTH and beta END/beta LPH responses similar to those after the first stress. Application of a second stress during the period of significant rate-rise of corticosterone in plasma did not result in decreased incremental responses of plasma ACTH or beta END/beta LPH. However, the rates of decline of plasma ACTH and beta END/beta LPH of 7.6 and 32 pM min-1, respectively, from peak levels, were significantly greater after this second stress applied during the period of significant increase in plasma corticosterone concentration than the corresponding rates of decline observed after the initial stress or after a subsequent stress applied at the peak of plasma corticosterone. These differences in rates of decline of plasma ACTH or beta END/beta LPH appear to reflect differences in secretion rate rather than clearance, since disappearance of [125I]ACTH1-24 was not different after an initial vs. subsequent stress. In contrast to these data from intact rats, initial and subsequent stresses did not show different rates of decline of plasma ACTH or beta END/beta LPH in adrenalectomized rats. In conclusion, the stress-induced rate rise of glucocorticoid provides a negative feedback signal which serves to terminate and limit the duration, but not the peak, of the responses of POMC-derived peptides to subsequent stress.

Epinephrine Suppresses Stress-Induced Increases in Plasma Immunoreactive β-Endorphin in Humans

The present study evaluated the hypothesis that increased plasma levels of epinephrine (EPI) stimulate immunoreactive beta-endorphin (i beta END) secretion in humans experiencing a mild stress. The stressor consisted of intraoral injections of a local anesthetic solution (with or without EPI) just before the surgical extraction of impacted third molars in 26 awake unsedated patients. The EPI group experienced a 30-fold increase in plasma EPI levels by 2 min after injection; these concentrations were physiologically active, as evidenced by increased pulse rate and systolic blood pressure. However, compared to a no EPI control group the EPI group had a significantly reduced i beta END response to the stressor, as evaluated by comparison of plasma levels at individual time points, maximal increases in plasma i beta END levels, and areas under the time-response curve. Whereas there was no association between plasma levels of EPI and i beta END in the EPI group (r = 0.119; P = NS), EPI and i beta END levels were strongly related in the no EPI group (r = 0.82; P less than 0.001). These results do not support the hypothesis of a stimulatory effect for EPI on i beta END release and, instead, suggest that an inhibitory relationship may exist in humans experiencing stress. The association between EPI and i beta END responses observed in the control group during this form of stress appears to be due to activation of a common central neural element.

Stimulation of β-Endorphin Secretion by Corticotropin-Releasing Factor in Primary Rat Leydig Cell Cultures*

CRF, a hypothalamic peptide, is a potent stimulator of POMC synthesis and secretion in the pituitary. POMC biosynthesis has been documented in the testis, specifically in Leydig cells, and recent studies suggest that CRF is synthesized locally in the testis. A reverse hemolytic plaque assay and immunocytochemistry with Leydig cell-specific antibodies were used to study the effect of CRF on secretion of the POMC peptide beta-endorphin (beta EP) from normal rat primary Leydig cell cultures. In enriched Leydig cell preparations incubated with beta EP antiserum (diluted 1:50) then with complement (diluted 1:25), approximately 15% of immunocytochemically identified Leydig cells formed plaques. Preabsorption of the antiserum with beta EP (2 micrograms/microliters antiserum) overnight at 4 C abolished the formation of plaques. Increasing concentrations of CRF (from 10(-1) to 10(-7) M) resulted in an approximately 80% increase in both the percentage of plaque-forming cells and the mean plaque size. When the CRF antagonist CRF-(9-41) (10(-6) M) was added in the presence of CRF, the increases in plaque number and average size did not occur. These results demonstrate that Leydig cells have functional CRF receptors and that beta EP secretion from these cells is stimulated by CRF.

Circadian, Ultradian, and Episodic Release ofβ-Endorphin in Men, and Its Temporal Coupling with Cortisol*

beta-Endorphin and ACTH derive from a common peptide precursor. Although much is known about the physiological patterns of ACTH release, neither the minute to minute regulation of beta-endorphin secretion nor its temporal relationship to cortisol has been characterized. As an initial step to defining the regulation of beta-endorphin release in man, we studied the circadian periodicity, ultradian rhythmicity, and episodic pulsatility of serum beta-endorphin concentrations in seven normal men. Blood sampling was conducted at 10-min intervals for 24 h, and the subsequent serum samples were assayed by a two-site immunoradiometric assay. Computerized analysis of the subsequent beta-endorphin time series revealed a mean beta-endorphin pulse frequency of 13 +/- 1 (+/- SE) peaks/24 h, corresponding to an interpulse interval of 100 +/- 7 min. The mean maximal peak height of beta-endorphin pulses was 31 +/- 3 pg/mL (9.0 +/- 0.8 pmol/L), which represented an incremental increase of 11 +/- 1 pg/mL 3.2 +/- 0.4 pmol/L; 63 +/- 13%) above the preceding nadir. The average beta-endorphin peak exhibited a duration of 68 +/- 6 min. Fourier analysis revealed a significant circadian amplitude of 6 +/- 1 pg/mL (1.6 +/- 0.4 pmol/L; 23% of the 24-h mean concentration), with an acrophase (time of maximum value) at 1043 h (+/- 40 min). Spectral analysis also disclosed beta-endorphin rhythms with mean periodicities of 29 +/- 4, 42 +/- 4, and 61 +/- 5 min. Gel filtration chromatography confirmed that serum beta-endorphin peaks contained significantly more immunoactive beta-endorphin [62 pg/mL (18 pmol/L)] than did the flanking nadirs [16 and 18 pg/mL (4.6 and 5.2 pmol/L)]. Auto- and cross-correlation analyses of serum beta-endorphin and cortisol concentrations followed by autoregressive modeling disclosed that all seven men had significant positive cross-correlations between serum beta-endorphin and cortisol considered simultaneously or when cortisol lagged beta-endorphin by 10 min. A negative cross-correlation was found in five of the seven men when cortisol was considered to lead beta-endorphin by 20 or 30 minutes. We conclude that beta-endorphin is released physiologically in a pulsatile manner with circadian and ultradian rhythmicity and a close temporal coupling to cortisol.

Onset of Glucocorticoid Responsiveness of Anterior Pituitary Corticotrophs during Development is Scheduled by Corticotropin-Releasing Factor

Expression of the CRF gene in the hypothalamus and that of the POMC gene in the anterior pituitary are reduced during the first week of life in the rat. During this so-called stress nonresponsive period (SNRP), stimuli such as ether vapors, electroshocks, and hypoxia do not elicit ACTH secretion from the pituitary, as occurs later in development. The current hypothesis to explain the SNRP is an increased negative glucocorticoid feedback on POMC and CRF synthesis and/or release during this time. To test this hypothesis we studied the effects of adrenalectomy (ADX) on anterior pituitary POMC mRNA expression. In 7-day-old rats POMC mRNA levels were increased only 3-fold 48 h post-ADX, compared to a 7-fold increase in 14-day-old animals. This blunted effect of endogenous glucocorticoid removal on pituitary POMC mRNA could be due to decreased up-regulation of CRF after removal of glucocorticoids or normal up-regulation of CRF but decreased pituitary responsiveness to CRF relative to those in 14-day-old animals. Therefore, we studied in vitro beta-endorphin release from pituitaries obtained from 7- and 14-day-old rats. CRF stimulated basal beta-endorphin release to the same extent in pituitaries from both groups. The inhibition by corticosterone of CRF-stimulated beta-endorphin secretion was also indistinguishable in pituitaries obtained from 7- or 14-day-old rats. Since the responsiveness of the 7-day-old pituitary was normal, the blunted enhancement of POMC biosynthesis after ADX must be mediated at the level of the hypothalamus. Indeed, in situ hybridization showed that while in 14-day-old rats ADX induced a significant increase [190 +/- 10% (+/- SE) of control; n = 5; P less than 0.0005] in hypothalamic mRNA levels, ADX did not change the expression of the CRF gene in the paraventricular nucleus of 7-day-old rats, indicating a lack of glucocorticoid modulation of hypothalamic CRF synthesis. Finally, we studied the effects of 48 h CRF treatment on the post-ADX increase in POMC mRNA levels in 7-day-old rats. Daily injections of 200 ng CRF/rat induced an increase in anterior pituitary POMC mRNA concentrations [669 +/- 139% (+/- SE) of control; n = 6; P less than 0.02 vs. adrenalectomized vehicle-treated rats] comparable to that in adrenalectomized untreated 14-day-old rats. In conclusion, our data indicate that the glucocorticoid regulation of hypothalamic CRF gene expression is not mature during the first week of life, i.e. within the so-called SNRP.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of IL-1 in the corticotropin-releasing factor and arginine- vasopressin-induced secretion of immunoreactive beta-endorphin by human peripheral blood mononuclear cells.

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) stimulate the secretion of beta-endorphin by human PBMC. It is shown here that peripheral blood B cells are responsible for the production of beta-endorphin after culture with CRF and AVP. The presence of CD14+ monocytes is, however, a prerequisite for the enhancing activity of CRF and AVP. The data presented here show that rIL-1 beta can replace CRF and AVP, whereas a mAb directed against IL-1 abrogates the response to CRF and AVP. These results indicate that IL-1 mediates the effect of CRF and AVP on beta-endorphin production by human PBMC.

Interleukin 1 potentiates the secretion of beta-endorphin induced by secretagogues in a mouse pituitary cell line (AtT-20).

Previous work has shown that corticotropin releasing factor, vasoactive intestinal peptide, phorbol ester, and forskolin cause the secretion of adrenocorticotropic hormone and beta-endorphin from the AtT-20 mouse pituitary cell line. Human recombinant interleukin 1 alpha and 1 beta also stimulated adrenocorticotropic hormone and beta-endorphin secretion from AtT-20 cells in a time- and dose-related manner. The effect appeared only after pretreatment with interleukin 1 (IL-1) for at least 18 hr and was maximum at 24 hr. After pretreatment of the cells over a period of time with IL-1, the secretion induced by corticotropin releasing factor and vasoactive intestinal peptide was increased in more than an additive manner. The enhancement of corticotropin releasing factor-induced beta-endorphin release produced by IL-1 was apparent after 12 hr and reached a maximum at 24 hr. IL-1 did not affect forskolin-induced cAMP generation but enhanced the effect of forskolin on beta-endorphin secretion. This suggests that IL-1 does not induce adenylate cyclase and that forskolin causes the secretion of beta-endorphin by a mechanism independent of cAMP. IL-1 enhanced phorbol ester-induced beta-endorphin secretion. After prolonged treatment with phorbol ester (an activator of protein kinase C), the secretion induced by phorbol ester was abolished as well as the enhancement induced by IL-1. However, prolonged treatment with phorbol ester had no effect on IL-1-induced beta-endorphin secretion. These observations suggest that IL-1 enhances peptide-generated secretion of beta-endorphin by inducing protein kinase C.

Quantitative Relationships Between Plasma Beta-Endorphin Immunoactivity and Hemodynamic Performance in Preoperative Cardiac Surgical Patients

To quantitate the importance of cardiac dysfunction as a stimulus for plasma immunoactive beta-endorphin (iBE) secretion, we measured iBE and hemodynamic indices in 65 patients prior to anesthetic induction for coronary artery bypass grafting or valve replacement. Linear regression analysis for the group as a whole showed significant correlations between iBE and stroke index (SI), pulmonary artery wedge pressure (PCW), and right atrial pressure (RAP), but not mean arterial pressure (MAP). Two patient subgroups were identified (P less than 0.001 by F-test): those with low SI and high iBE, or those with high SI and low iBE (cutoffs at 40 ml/m2 and 35 pg/ml, respectively). Correlations between hemodynamics and iBE were always stronger within the low-SI than the high-SI subgroups. These correlations were greater for patients with coronary artery than with valvular heart disease. Cardiac output (CO) and cardiac index (CI) correlated with iBE in valve-replacement and coronary-grafting groups. These findings were not an artifact of impaired iBE clearance due to renal dysfunction. Our results quantitate the importance of hemodynamic dysfunction for iBE secretion, and indicate that this relationship is particularly strong when stroke index declines below 40 ml/m2.

Plasma beta-endorphin, ACTH and cortisol secretion in man after nasal spray administration of calcitonin

Beta-endorphin, ACTH and cortisol secretion were measured in twelve healthy adult males after nasal spray administration 200 IU salmon calcitonin. A significant increase in plasma beta-endorphin, from 19.2 ng/l under basal conditions to a peak of 27.1 ng/l at 30 min was recorded. Plasma ACTH and cortisol were not affected. In individual subjects the beta-endorphin level was increased in eight of the twelve, ACTH rose in three and cortisol did not change in any of them. The data indicate that calcitonin induced a beta-endorphin increase independent of enhanced corticotrophin-cortisol release.

Release from Inflamed Tissue of a Substance with Properties Similar to Corticotropin-Releasing Factor

In response to stressors involving tissue injury, pituitary corticotroph secretion of immunoreactive beta-endorphin (iB-END) could be either due to release of hypothalamic factors such as corticotropin-releasing factor (CRF) or to release of a tissue factor from the periphery. In the present experiments, we investigated whether inflamed tissue releases a factor which evokes pituitary secretion of iB-END. In an initial experiment, rats with an inflamed hindpaw due to carrageenan injection had significantly greater levels of circulating iB-END as compared to rats with saline-injected paws. Removal of afferent input, by hindlimb denervation, failed to block the carrageenan-induced increase in iB-END levels. Subcutaneous perfusates were then collected from inflamed and control hindlimbs and applied to rat anterior pituitary cell cultures. Pituitary release of iB-END due to administration of perfusate from inflamed paws was significantly greater than iB-END release due to perfusate from saline-injected paws or to basal release. The releasing activity in the perfusates was blocked in calcium-free medium and was not due to a direct action of carrageenan, bradykinin, substance P or calcitonin gene-related peptide. The results indicate that inflamed tissue releases a CRF-like factor which stimulates iB-END release both in the denervated rat and cultured pituitary cells.

Effect of Atrial Natriuretic Peptide on the Release of .BETA.-Endorphin from Rat Hypothalamo-Neurohypophysial Complex.

The aim of this study was to determine whether atrial natriuretic peptide (ANP) alters beta-endorphin (beta-END) secretion from rat intermediate pituitary and whether this effect is a direct action on the intermediate pituitary or an indirect one mediated by hypothalamic factor(s). We studied the release of beta-END from rat neuro-intermediate lobes of the pituitary (NIL) and from the hypothalamo-neurohypophysial complex (HNC), which consists of the hypothalamus, pituitary stalk, intermediate and posterior lobes of the pituitary, by means of an in vitro perifusion system. NIL and HNC were prepared from male Wistar rats and individually perifused for 30 min with perifusion medium followed by 20 min perifusion with medium containing alpha-rat ANP and/or dopamine (DA). Samples of perifusion medium were collected every 5 min and subjected to RIA for beta-END. The basal release of beta-END from NIL was 180% of that from HNC (p less than 0.01), which provides further support for the presence of hypothalamic factors that inhibit beta-END release from the intermediate pituitary. The perifusion of HNC with ANP at 10(-7) and 10(-6) M increased the beta-END concentration by 25 and 50%, respectively (p less than 0.01). In contrast, ANP (10(-8) to 10(-6) M) had no effect on beta-END release from NIL. The inhibitory effect of DA (10(6) M) on beta-END release from NIL and HNC (51% and 50% of the basal release, respectively, p less than 0.01) was confirmed. However, this inhibitory effect was not reversed by ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of contrast media on beta-endorphin secretion

The central nervous system may be highly susceptible to the toxic effects of contrast media (CM). Previous experiments demonstrated that vasopressin is released after the intravenous administration of CM. the present study examined the response of the opiocortin system to CM. Neurons of the rat basal hypothalamus, dispersed and attached to Cytodex-3 beads, were perfused with sodium diatrizoate, metrizamide or iohexol (3 mg iodine/ml). the effluent was collected, and the beta-endorphin (B-E) content was measured by a radioimmunoassay technique. Results, normalized to the internal positive control, were compared with release from normal saline (negative control) by analysis of variance. Diatrizoate and metrizamide caused significant release of B-E (p <0.03). Iohexol did not stimulate release of B-E. These results suggest that diatrizoate and metrizamide, but not iohexol, can stimulate the release of hormones from hypothalamic neurons. the phenomenon may play a role in some reactions to intravascular CM admi...

Effect of Contrast Media on Beta-Endorphin Secretion

The central nervous system may be highly susceptible to the toxic effects of contrast media (CM). Previous experiments demonstrated that vasopressin is released after the intravenous administration of CM. The present study examined the response of the opiocortin system to CM. Neurons of the rat basal hypothalamus, dispersed and attached to Cytodex-3 beads, were perfused with sodium diatrizoate, metrizamide or iohexol (3 mg iodine/ml). The effluent was collected, and the beta-endorphin (B-E) content was measured by a radioimmunoassay technique. Results, normalized to the internal positive control, were compared with release from normal saline (negative control) by analysis of variance. Diatrizoate and metrizamide caused significant release of B-E (p &lt; 0.03). Iohexol did not stimulate release of B-E. These results suggest that diatrizoate and metrizamide, but not iohexol, can stimulate the release of hormones from hypothalamic neurons. The phenomenon may play a role in some reactions to intravascular CM administration since these neurons are not protected by a blood-brain barrier.

Antiserotonergic inhibition of calcitonin-induced increase of beta-endorphin, ACTH, and cortisol secretion.

In a previous study we observed that calcitonin increases beta-endorphin, ACTH, and cortisol secretion. We assumed that calcitonin might have a modulatory role on the pituitary function. The present study was initiated to clarify whether this effect is due to a direct pituitary stimulation or to an indirect stimulation through CRF (corticotropin releasing factor). Fourteen healthy subjects, aged 30-60 years were investigated. All the subjects received 100 IU Salmon calcitonin Sandoz i.v. at 8 a.m. (time 0). Plasma beta-endorphin, ACTH and cortisol were estimated every 30 min from -30 to 120 min by specific radioimmunoassay. The same parameters were estimated a second time, at the same intervals, when cyproheptadine 8 mg (7 subjects) and 40 mg propranolol (7 subjects) were given per os at -30 min and calcitonin i.v. at time 0. beta-endorphin, ACTH and cortisol levels (Mean +/- SEM) rose significantly after calcitonin (peak value at 30-90 min) from 5.2 +/- 0.7 to 15.1 +/- 2.6 pmol/l; from 43.0 +/- 2.7 to 70.7 +/- 4.1 pg/ml and from 10.6 +/- 1.5 to 19.6 +/- 2.1 micrograms/100 ml respectively (p less than 0.0001 by analysis of variance and covariance and repeated measures). Propranolol 40 mg (per os) administered at time -30 did not alter the response of beta-endorphin, ACTH and cortisol to calcitonin (infused at time 0). Cyproheptadine, the antiserotonergic substance that inhibits the synthesis and release of CRF completely inhibited the stimulatory effect of calcitonin. We conclude that probably calcitonin has a modulatory role on the hypothalamo-pituitary adrenal axis and that it acts at the hypothalamic level probably by stimulating CRF secretion.

Impaired beta-endorphin response to human corticotropin-releasing hormone in obese children.

In order to evaluate the secretion of beta-endorphin in obese children and adolescents, we measured plasma beta-endorphin, ACTH and cortisol levels before and following administration of CRH (1 microgram/kg). Fourteen normal weight and 22 obese subjects (weight excess ranging from 30 to 98%) were studied. Plasma hormone levels were measured by radioimmunoassay directly in plasma (cortisol, ACTH) and after silicic acid extraction and Sephadex G-75 column chromatography (beta-endorphin). Basal beta-endorphin levels in obese children were significantly higher than in controls (14.7 +/- 1.8 vs 6.0 +/- 0.6 pmol/l; mean +/- SEM). No differences were found in basal ACTH and cortisol levels. CRH administration significantly increased beta-endorphin, ACTH and cortisol levels in normal subjects and ACTH and cortisol levels in obese subjects. Plasma beta-endorphin levels in obese children and adolescents did not show any significant increment. These data confirm the higher than normal beta-endorphin plasma levels in obese subjects in childhood and demonstrate that CRH is unable to increase beta-endorphin levels, suggesting an impairment of the hypothalamo-pituitary control mechanisms or an extra-anterior pituitary source.

Neuroimmunomodulation in cancer patients: correlations between melatonin and beta-endorphin blood levels and T helper/suppressor ratio.

The pineal gland and opioid peptides play roles in the neuroendocrine control of immunity. Both neuroendocrine and immune dysfunctions have been observed in cancer but the importance of the altered secretion of neurohormones in the immunoincompetence of cancer patients has never been investigated. This study concomitantly evaluated neuroendocrine and immune functions in 40 patients with early or advanced neoplastic disease. In each patient, melatonin and beta-endorphin blood levels and lymphocyte subtypes were determined on venous blood samples collected during the morning. Metastatic patients had lower melatonin levels and a lower T4/T8 ratio than patients without metastases but no significant correlation was found between melatonin and the T4/T8 ratio. beta-endorphin levels appeared to be normal in all patients. These results suggest that melatonin and beta-endorphin secretion have no role in determining immune dysfunctions in cancer.