beta-Endorphin: development of tolerance and its reversal by 5-hydroxytryptophan in cats.

Tolerance to beta-endorphin developed acutely in cats if the administration of the peptide was repeated within the first 24 hr. The tolerance was reversed immediately by systemic administration of the serotonin precursor, 5-hydroxytryptophan. It was further shown that 5-hydroxytryptophan potentiates the analgesic effect of the subliminal dose of beta-endorphin.     

beta-Endorphin: surface binding and internalization in thymoma cells.

The opioid peptide beta-endorphin binds to specific nonopioid binding sites (Mr 72,000) that are present on the surface of thymoma cells. beta-Endorphin is then internalized, apparently via the Mr 72,000 species, and is subsequently found within intracellular, vesicular structures. This process is accompanied by the down-regulation of the Mr 72,000 binding sites. Our findings suggest that beta-endorphin may modulate cellular functions, such as T-lymphocyte proliferation, at intracellular rather than cell surface sites.     

beta-Endorphin in the human pancreas.

Using a specific antiserum, beta-endorphin was quantitated in 8 human pancreas obtained at autopsy by radioimmunoassay and localized by immunocytochemistry. The mean (+/- SE) concentration of beta-endorphin in pancreatic extracts of 5 non-diabetic adults was 13.5 +/- 9.8 ng/gm with a range of 2.1 to 52.8 ng/gm of tissue. Pancreatic beta-endorphin concentration in two premature infants were within the range found in adults. In one diabetic pancreas, there was no measurable beta-endorphin. Specific beta-endorphin immunofluorescence is localized within the pancreatic islets. This finding suggests that beta-endorphin may participate in intraislet regulation of pancreatic hormone secretion.     

beta-Endorphin: formation of alpha-helix in lipid solutions.

Human beta-endorphin adopts a partial helical conformation in aqueous solutions of cerebroside sulfate, ganglioside GM1, phosphatidylserine, and phosphatidic acid, but not of cerebroside and phosphatidylcholine, as evidenced by circular dichroic spectra. Addition of Ca2+ to the peptide in cerebroside sulfate solution can break up the helix; at 10 mM Ca2+ the peptide (12 microM) essentially exists in an unordered form. For comparison, sheep beta-lipotropin in acidic cerebroside sulfate solution (pH less than 4) also has a partial helical conformation of the complex between human beta-endorphin and lipids may be related to the opiatelike function of this peptide hormone.     

beta-Endorphin enhances lymphocyte proliferative responses.

The opioid peptides alpha- and beta-endorphin and [D-Ala2, Met5]enkephalin were investigated for their effect on the proliferation of resting and activated rat splenic lymphocytes in vitro. beta-Endorphin enhanced the proliferative response of spleen cells to the T cell mitogens concanavalin A and phytohemagglutinin. The effect of beta-endorphin was dose dependent and occurred at peptide concentrations similar to those found in rat plasma. alpha-Endorphin and [D-Ala2, Met5]enkephalin did not affect the proliferative responses to any mitogen tested. Furthermore, the potentiating effect of beta-endorphin was not reversed by treatment with 10 microM naloxone. None of the peptides had any effect on resting, unstimulated spleen cells or on the response to a mixture of lipopolysaccharide and dextran sulfate, which is specifically mitogenic for B lymphocytes. The pharmacological properties of the beta-endorphin potentiation indicate that the effect may be mediated by a nonopiate but beta-endorphin-specific mechanism. These results suggest a possible role for peripheral beta-endorphin and may provide a link between stress and disease susceptibility.     

beta-Endorphin and cortisol abnormalities in spinal cord-injured individuals.

Plasma beta-endorphin-like immunoreactivity (BEP-ir) and cortisol levels were measured by radioimmunoassay (RIA) in nine patients who were at least 12 months status post spinal cord injury (SCI). Plasma levels were obtained at 8:00 am and 4:00 pm to determine circadian rhythm, and on the day following administration of 1 mg dexamethasone, levels were again obtained at 8:00 am and 4:00 pm. The mean morning levels of plasma BEP-ir were significantly lower than control values for this laboratory (6.2 +/- 1.2 v 12.0 +/- 2.3 pg/mL). The morning BEP-ir values were lowest in patients who were closer to the time of injury (described by a second-order polynomial regression, R = .89; P less than .01). Mean morning cortisol levels were not significantly different from controls, but showed greater variability (mean, 15.1; range, 0.7 to 22.7 micrograms/dL v control, 15.5; range, 7 to 35). Dexamethasone suppressed cortisol secretion in all patients and BEP-ir levels in six of nine patients. Failure to detect BEP-ir suppression occurred in patients whose BEP-ir levels were less than 4.5 pg/mL and close to the minimum detection limit of the assay. Depression was present in five of nine patients as measured by the Beck Depression Inventory (BDI) and in three of nine patients as measured by the Hamilton Depression Scale (HSRD). However, the depression indices did not correlate with the neuroendocrine measures.     

beta-Endorphin: pituitary and adrenal glands modulate its action.

Hypophysectomized rats are supersensitive to the hypothermic effects of morphine and beta-endorphin injected intraventricularly as early as 1 week after surgery. At 2 weeks after surgery, there is a significant increase in the antinociceptive potency for these opiates. The route of opiate injection must be considered in interpretations of these results. The enhanced opiate potency following subcutaneous morphine injection in hypophysectomized rats may be partially explained by adrenal dysfunction, as demonstrated by a similar sensitization to subcutaneous morphine following adrenalectomy. By contrast, no enhancement of opiate potency was observed upon direct intraventricular injection of morphine or beta-endorphin in adrenalectomized rats. Furthermore, the potency of intravenous beta-endorphin is profoundly enhanced in adrenalectomized mice; five out of nine animals died when injected with a dose of the peptide that produced only mild analgesia in sham controls. The complete reversal of this intravenous beta-endorphin supersensitivity by dexamethasone implies a possible physiological interplay between the peptide and adrenal function.     

beta-Endorphin induces nonconvulsive limbic seizures.

The endogenous opioid peptide, beta-endorphin, induces nonconvulsive limbic epileptiform activity when administered intraventricularly to rats. Epileptiform activity is elicited by beta-endorphin in doses that are devoid of analgesic or behavioral signs. Equimolar intraventricular doses of morphine or of the enkephalin analog [DAIa2,Met5]enkephalin-NH2 fail to elicit this limbic epileptiform activity. These observations, together with the recent immunohistochemical localization of beta-endorphin to midline limbic structures, suggest that beta-endorphin may have an important role in the regulation of limbic excitability.     

beta-Endorphin: demonstration of a tertiary structure in aqueous solution.

Difference spectra generated during thermolysin digestion of camel beta-endorphin at pH 8.2 or at pH 6.5 indicate rapid blue shifting of the near-UV absorption bands of the NH2-terminal tyrosine. A similar spectral change is not observed for the NH2-terminal tyrosine in [Met]enkephalin when it is digested under similar conditions. These results suggest that enzymatic digestion destroys or alters some structural interaction between the NH2-terminal tyrosyl residue of the endorphin and a residue(s) within the COOH-terminal segment of the molecule. Peptide mapping of the digest as a function of time suggests that cleavage of the bond linking the alanine-21 and isoleucine-22 residues produces most of the observed effect. These data provide evidence for the existence of a tertiary structure for beta-endorphin in aqueous solutions.     

beta-Endorphin: characteristics of binding sites in rabbit spinal cord.

The interaction of human beta-endorphin with binding sites in rabbit spinal cord has been characterized. The stereospecific high-affinity binding sites are concentrated in the dorsal half of the spinal cord. Scatchard analysis of the binding data shows heterogeneity of the binding sites that can be resolved into two populations with apparent dissociation constants of 3.0 (+/-2.0) X 10(-10) and 3.3 (+/- 0.5) X 10(-9) M. Sodium ions decrease the binding of human beta-endorphin to spinal cord to the same extent as found in rat brain. The ability of several opiates and opioid peptides to inhibit the binding of human beta-endorphin is also presented.     

beta-Endorphin: cross tolerance to and cross physical dependence on morphine.

The effects of beta-endorphin on the antinociceptive responses and abrupt withdrawal jumping in morphine-dependent mice were studied. Mice were rendered morphine dependent by implantation of a morphine pellet (75 mg base) for 3 days. The analgesic response to beta-endorphin decreased after morphine pellet implantation, as evidenced by an eight-fold increase in the median antinociceptive dose of morphine was found. In small doses (0.09-0.17 mug per mouse), beta-endorphin suppressed abrupt withdrawal jumping. Met-enkephalin, even in high doses (200 mug per mouse), did not suppress abrupt withdrawal jumping.     

beta-Endorphin: characteristics of binding sites in a neuroblastoma--glioma hybrid cell.

Specific binding of human beta-endorphin to NG108-15 cells is described; human beta-[Tyr27-3H2] endorphin was used as the ligand. The binding is time dependent and saturable; Kd = 0.3 nM and ka = 1.8 x 10(8) M-1 min-1. Under the conditions optimal for beta-endorphin binding, leucine-enkephalin has one-fourth to one-third as many binding sites as beta-endorphin and its affinity is 7--10% that of beta-endorphin. Monovalent and divalent cations potently inhibit binding. Trypsin, phospholipase A, and N-ethylmaleimide reduce the ability of NG108-15 cells to bind beta-endorphin. beta-Endorphin analogs are able to fully inhibit the binding of beta-[Tyr27-3H2]endorphin, although enkephalins, morphine, and naloxone inhibit only 50--80%.     

Beta-Endorphin: dissociation of receptor binding activity from analgesic potency.

Biological activities of synthetic camel beta-endorphin and human beta-endorphin (beta h-EP) have been measured by the radioreceptor binding assay, using [Tyr27-3H]-beta h-EP as the primary ligand and by the tail-flick test for analgesic potency. Four synthetic analogs of beta h-EP, namely [Gly31]-beta h-EP-Gly-NH2, [Gly31]-beta h-EP-Gly-Gly-NH2, [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2, and [CH3(CH2)4NH231]-beta h-EP, have also been assayed by the same procedures. Results indicate a clear dissociation of radioreceptor binding activity from analgesic potency.     

beta-Endorphin omission analogs: dissociation of immunoreactivity from other biological activities.

An analog of human beta-endorphine with omission of four residues at positions 11, 14, 20, and 22 has been synthesized. This analog and other synthetic analogs with deletion of a single amino acid at position 2, 5, 6, 10, 11, 12, 13, 15, or 22 have been assayed for analgesic potency, ileal opiate activity,opiate receptor-binding activity, andimmunoreactivity. Results show that deletion of a single amino acid of the beta-endorphin molecule outside of the enkephalin segment to give des-Gln11-, des-Thr12, des-Pro13-, des-Leu14-, des-Val15-, des-Asn20-, or des-Ile22-beta-endorphin markedly reduced or abolished the immunoreactivity yet gave substantial retention of opiate potencies. Deletion of a single amino acid of beta-endorphin within the enkephalin segment (des-Gly3- or des-Met5-beta-endorphin) did not markedly affect the immunoactivity; however, the opiate activities were abolished or markedly reduced. The data indicate a clear dissociation of immunoactivity from analgesic, ileal-opiate, and opiate receptor-binding activities.     

beta-Endorphin and beta-lipotropin plasma levels in hirsute women: correlation with body weight

Based on the findings of elevated circulating beta-endorphin (beta-END) levels in genetically obese (fa/fa) fats and the reversal of the overeating of genetically obese (ob/ob) mice by naloxone, circulating beta-END and beta-lipotropin (beta-LPH) levels were measured in 8 hirsute, hyperandrogenic, oligo-amenorrheic women of varying weights. Circulating beta-END and beta-LPH levels were significantly elevated (p less than .001) above the levels in nonobese control subjects and were positively correlated with body weight (p less than .025). Based on these data and indirect evidence in the literature, we propose a role may exist for beta-END and/or beta-LPH in human obesity and in adrenal androgen secretion.     

beta-Endorphin in hypophyseal portal blood: variations throughout the menstrual cycle

Concentrations of beta-endorphin were measured in the venous effluent of the hypothalamus (hypophyseal portal blood) at various phases of the menstrual cycle and after ovariectomy in rhesus and pigtailed monkeys. In the rhesus, beta-endorphin concentrations were high during the mid- to late follicular phase [737 +/- 256 pg/ml (mean +/- SE)] and the luteal phase (1675 +/- 1108) of the menstrual cycle, but were undetectable (less than 133) at menstruation. Concentrations were also high in pigtailed monkeys during stages of the menstrual cycle other than at menstruation (4870 +/- 1090 pg/ml), but undetectable (less than 133) 4--12 months after ovariectomy. These results indicate that beta-endorphin concentrations in hypophyseal portal blood are related to menstrual cycle events, probably changes in ovarian steroids; this in turn suggests that beta-endorphin may participate in the ovarian feedback regulation of gonadotropin secretion.     

beta-Endorphin: synthesis of analogs modified at the carboxyl terminus with increased activites.

Three analogs of human beta-endorphin (beta h-EP) have been synthesized: [Gly31]beta h-EP, [Gly31]beta h-endorphinamide, and [Gly31]beta h-endorphinylglycine. All are more active than beta h-EP in both the guinea pig ileum bioassay and the opiate receptor binding assay. The last two analogs are about twice as active as beta h-EP in an assay for analgesia. Modification at position 31 and extension at the COOH terminus may afford a route toward analogs with even greater biological activity.     

十二指肠溃疡与血浆促胃动素和β内啡肽关系的临床研究

目的探讨十二指肠溃疡(DU)与血浆促胃动素(MTL)和p内啡肽(β-EP)的关系.方法用放射免疫法测定活动期DU、疤痕期DU患者及健康对照组的血浆MTL和β-EP浓度,并进行比较分析.结果活动期DU及疤痕期DU患者的血浆MTL浓度均明显低于正常对照组(活动期DU153.79ng/L±42.20ng/L,疤痕期DU154.96ng/L±46.32ng/L,正常对照组190.49ng/L±36.54ng/L).活动期DU患者的血浆β-EP浓度明显高于正常对照组,而疤痕期DU患者的血浆β-EP浓度与正常对照组无显著差异(活动期DU12.56ng/L±4.62ng/L,疤痕期DU9.11ng/L±4.09ng/L,正常对照组8.92ng/L±3.45ng/L).结论DU患者的血浆MTL浓度降低和β-EP浓度升高可能参与DU发生、发展的病理生理过程.