Cerebrospinal Fluid Β-endorphin Research Articles

The Melanocortin and Endorphin Neuropeptides in Patients with Restless Legs Syndrome.

Based upon similarities between the urge to move and sensory discomfort of restless legs syndrome (RLS) and properties of melanocortin hormones, including their incitement of movement and hyperalgesia, we assessed plasma and cerebrospinal fluid (CSF) α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in RLS patients and controls. Forty-two untreated moderate-to-severe RLS patients and 44 matched controls underwent venipuncture at 19:00, 20:30, and 22:00; 37 RLS and 36 controls had lumbar puncture at 21:30. CSF and plasma were analyzed for pro-opiomelanocortin (POMC), adrenocorticotropin hormone (ACTH), α-MSH, β-MSH, and β-endorphin by immunoassay. RLS severity was assessed by International RLS Study Group Severity Scale. RLS participants were 52.7 ± 12.0 years old, 61.9% were women, 21.4% had painful RLS, and RLS severity was 24.8 ± 9.0. Controls had similar age and sex. Plasma ACTH, α-MSH, and β-endorphin were similar between groups. Plasma POMC was significantly greater in RLS than controls (17.0 ± 11.5 vs 12.7 ± 6.1fmol/ml, p = 0.048). CSF ACTH was similar between groups. CSF β-MSH was significantly higher in painful than nonpainful RLS or controls (48.2 ± 24.8 vs 32.1 ± 14.8 vs 32.6 ± 15.2pg/ml, analysis of variance [ANOVA] p = 0.03). CSF α-MSH was higher in RLS than controls (34.2 ± 40.9 vs 20.3 ± 11.0pg/ml, p = 0.062). CSF β-EDP was lowest in painful RLS, intermediate in nonpainful RLS, and highest in controls (8.0 ± 3.4 vs 10.8 ± 3.1 vs 12.3 ± 5.0pg/ml, ANOVA p = 0.049). The ratio of the sum of CSF α- and β-MSH to CSF β-endorphin was highest, intermediate, and lowest in painful RLS, nonpainful RLS, and controls (p = 0.007). CSF β-MSH is increased and CSF β-endorphin decreased in RLS patients with painful symptoms. ANN NEUROL 2024;95:688-699.

Plasma and Cerebrospinal Fluid Beta-Endorphin Levels Show a Strong Association in Children with Cerebral Malaria.

Background:Beta (β)-endorphins are endogenous neuropeptides found in the plasma and cerebrospinal fluid (CSF) of humans but there have been reports of the relationship between the plasma and CSF β-endorphin levels in different clinical conditions. However, the relationship between β-endorphin levels in the plasma and CSF of children with cerebral malaria (CM) has not been reported.Aim:To determine the relationship between β-endorphin levels in the CSF and plasma of children with CM.Settings and Design:This cross-sectional study involved 40 children, aged between 6 months and 14 years, admitted with a diagnosis of CM at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria.Materials and Methods:One milliliter (mL) of venous blood and 1mL of CSF obtained from each subject at admission were used to determine the β-endorphin levels using enzyme-linked immunosorbent assay (ELISA) method.Statistical Analysis:Bivariate linear regression was used to determine the association between plasma and CSF β-endorphin levels using the correlation coefficient (r), coefficient of determination (R2), and P values.Results:The plasma β-endorphin levels significantly positively correlated with CSF β-endorphin (r = 0.568, P = 0.001) such that for every unit rise in plasma β-endorphin, CSF β-endorphin rose by 0.252 pmol/L (confidence interval: 0.132–0.371 pmol/L).Conclusion:The finding of positive correlation between plasma and CSF β-endorphin levels in this study suggests a possible direct link between plasma and CSF in CM, probably from the disruption of the blood–brain barrier that has been reported in CM.

Effects of taste stimulation on β-endorphin levels in rat cerebrospinal fluid and plasma

Opioids are suggested to be involved in generation of palatability and facilitation of consumption of food and fluid. We measured the level of an endogenous opioid, β-endorphin, in the cerebrospinal fluid (CSF) and plasma after free drinking of water and taste solutions in Wistar rats. When the water-deprived animals were allowed to drink 10 mL of water, the level of β-endorphin increased significantly 60 and 90 min after the start of drinking in both samples. β-Endorphin in the CSF increased most after ingestion of 0.5 M sucrose and 0.005 M saccharin followed by 0.1 M NaCl, 0.1 mM quinine and water. An intragastric infusion of 7 mL of water did not change the β-endorphin level. Essentially the same results were obtained for plasma samples except that NaCl and quinine solutions did not increase β-endorphin levels. Sucrose became ineffective in releasing β-endorphin in both samples after the establishment of conditioned taste aversions to this taste stimulus. These results suggest that the release of β-endorphin is positively correlated with the palatability of taste stimuli, and that CSF β-endorphin also reflects the reinforcement of fluid intake in thirsty animals.

CSF ACTH and β-endorphin in infants with West syndrome and ACTH therapy

Corticotrophin (adrenocorticotropic hormone, ACTH) and β-endorphin levels of the cerebrospinal fluid (CSF) were determined in 16 infants with the West syndrome during individualized ACTH treatment. Prior to treatment, the levels of CSF ACTH were significantly higher in infants with cryptogenic spasms, normal perinatal events, or normal development than in infants with symptomatic spasms or delayed development. The CSF β-endorphin levels did not differ among the groups. At response, the infants could be divided into three groups: (1) short-course, low-dose responders with a substantial CSF ACTH decline, (2) long-course, high-dose responders with no such effect (but with a tendency towards an upward incline), and (3) non-responders with no significant CSF ACTH changes. The changes in CSF β-endorphin were somewhat similar to the changes in CSF ACTH, but the greater variability did not allow statistical significance.

Cerebrospinal fluid β-endorphin in models of hyperalgesia in the rat

Cerebrospinal fluid (CSF) obtained by acute percutaneous puncture of the cisternal membrane of the halothane anesthetized rat has low but measurable concentrations of β-endorphin-like immunoreactivity (β-EPir: 32.8 ± 3.0 pmol/l). Chromatographic separation of β-EPir showed that authentic β-endorphin 1–31 was the main component of β-EPir in cisternal CSF. Subcutaneous injection of 5% formalin in the hind paws did not increase β-EPir in cisternal CSF. Rats with tactile paw hyperalgesia evoked by unilateral ligation of the L 5/6 nerve roots 2 weeks earlier had β-EPir concentrations that did not differ from sham operated or unoperated control animals. In contrast, capsaicin injected in the hindpaws increased the mean β-EPir concentration compared to saline injections ( P = 0.006) 45 min after emerging from anesthesia following injection. These results show that acute activation of C fibers (by capsaicin) will evoke the release of β-endorphin into the CSF, suggesting activation of the β-endorphin terminal systems in the brain/midbrain. The failure of formalin injections to release β-EPir to CSF may be due to specificity of the afferent stimulus evoking β-EPir release, a lower stimulus intensity, and/or the duration of the stimulus generated by formalin. The normal concentrations of β-EPir found in the hyperalgesic state following nerve injury suggest that the supraspinal β-endorphin system does not display tonic changes under such conditions.

Alterations in plasma and cerebrospinal fluid levels of neuropeptides in idiopathic senile anorexia.

Plasma and cerebrospinal fluid (CSF) concentrations of three well-known satiety neuropeptides, cholecystokinin (CCK), somatostatin and calcitonin gene-related peptide (CGRP), along with two powerful orexigenic neuropeptides, neuropeptide Y (NPY) and beta-endorphin have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF immunoreactivity levels of the two main fractions of CCK (CCK8s and CCK33) after being separated by HPLC were measured by a radioimmunoassay (RIA) developed in our laboratory, whereas the other neuropeptides were assayed by commercially available RIA kits. Elderly underweight anorectic patients had significantly lower levels of beta-endorphin but increased concentrations of NPY in both plasma and CSF when compared to controls. In addition to significantly higher levels of CCK8s but not CCK33 in plasma, we found a trend to higher CSF concentrations of CCK8s and a positive correlation between the body mass index and either beta-endorphin (r = 0.58, P < 0.05) or CCK8s (r = 0.69, P < 0.01) concentrations in CSF in the anorectic group. CSF somatostatin concentrations were decreased significantly, but plasma somatostatin levels and plasma and CSF concentrations of CGRP were similar in senile anorectics and controls. Treatment of five anorectic patients with megestrol acetate, 480 mg daily for 6 months, reversed only the decrease in CSF beta-endorphin levels but did not normalize the body weight or the fat body mass. On the basis of our findings, we hypothesize that a decrease in CSF beta-endorphin concentration along with a rise in plasma levels of CCK8s might be accounted for the primary anorexia of aging.

Plasma and cerebrospinal fluid β-endorphin in chronic tension-type headache

Previous studies have provided evidence of an increased sensitivity to pain, a decreased hypothalamic opioid tone, and decreased cerebrospinal fluid (CSF) β-endorphin (β-EP) concentration in patients with primary chronic headache. We applied separate specific radioimmunoassays for β-EP in CSF and plasma on samples from age-matched controls and a group of 50 patients with chronic tension-type headache (CTH) fulfilling the diagnostic criteria set by the International Headache Society. Median CSF β-EP concentrations (95% confidence limits) were 12.8 pmol/1 (11.0–14.5) in CTH patients and 11.9 pmol/1 (10.9–14.2) in the control group, which is not significantly different ( P = 0.28). Plasma β-EP concentrations did not differ either, being 3.1 pmol/1 (2.4–3.7) and 3.3 pmol/1 (1.8–4.0) in the patients with CTH and in controls, respectively ( P = 0.88). Plasma and CSF β-EP concentrations did not correlate. Reversed-phase high performance liquid chromatography (HPLC) of CSF pools from the headache patients and controls revealed similar profiles of β-EP-immunoreactivity both when C-terminally and N-terminally directed antisera were used, suggesting a normal post-translational processing of the pro-opiomelanocortin gene in patients with CTH. β-EP is not involved in the pathogenesis of CTH, or such a role is not reflected in CSF or plasma concentrations of the neuropeptide.

Evidence of alpha- N-acetyl β-endorphin in human cerebrospinal fluid

Alpha- N-acetyl-β-endorphin (Ac-β-EP) is a post-translational product of β-endorphin (β-EP) with no analgesic properties. Ac-β-EP is present in human fetal and adult pituitary gland and cross-reacts in all available β-EP assays. This study evaluates levels of Ac-β-EP in the cerebrospinal fluid (CSF) of 22 normal subjects and 15 chronic headache sufferers. Since dopamine may play a role in the acetylation process, homovanillic acid levels were also determined. After extraction and high performance liquid chromatographic (HPLC) fractionation of CSF, an immunoreactive Ac-β-EP peak was detected coeluting with reference peptide, Ac-β-EP was detectable in all but 5 normal subjects. In headache sufferers, Ac-β-EP levels were always detectable and their mean value was significantly higher than that of healthy subjects (11.6 ± 11.8 vs 3.9 ± 3.6 fmol/ml; P < 0.01). Conversely, CSF β-endorphin (β-EP) concentrations were decreased in headache patients (9.8 ± 9.4 vs 15.7 ±9.7 fmol/ml; P < 0.05), and as a consequence the β-EP/Ac-β-EP ration was also markedly reduced ( P < 0.005). No difference was observed for CSF homovanillic acid concentrations.These data demonstrate that HPLC coupled to radioimmunoassay allows the identification of low but significant amounts of Ac β-EP in human CSF. This compound represents a confounding factor when β-EP immunoreactivity is assessed by conventional methods. In headache sufferers, Ac-β-EP levels were higher than normal, whereas β-EP concentrations were lower. This finding may thus be evidence for a lability factor, possibly worsening pain susceptibility in chronic headache sufferers.

Correlation between cerebrospinal fluid phenylalanine and β-endorphin in patients with phenylketonuria

Previous animal and human studies have suggested an analgesic effect of phenylalanine involving endogenous opioid peptides. Phenylalanine was measured by a HPLC method with electrochemical detection and β-endorphin by a specific radioimmunoassay in 14 lumbar cerebrospinal fluid samples from 13 patients with phenylketonuria. Cerebrospinal fluid β-endorphin was also determined in 6 age-matched control subjects. We found a trend towards a higher β-endorphin level in phenylketonuria (median 26.0 pM, range 13.0–37.8) than in the control subjects (20.6 pM, 12.7–28.0), P = 0.13. Cerebrospinal fluid concentrations of phenylalanine and β-endorphin were significantly correlated ( r = 0.68, P = 0.008). The results support the hypothesis that phenylalanine modifies the central endogenous opioid system.

β-Endorphin in Cerebrospinal Fluid and Serum after Severe Head Injury

β-Endorphin in Cerebrospinal Fluid and Serum after Severe Head Injury

Relationship between cerebrospinal fluid β-endorphin and plasma pituitary-gonadal hormone levels in women

Brain beta-endorphin (beta-EP) plays an important role in regulating the hypothalamus-pituitary-gonadal axis activity. Cerebrospinal fluid (CSF) beta-EP levels seem to reflect the central rather than pituitary secretion. With the aim to correlate the changes of plasma estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone with brain beta-EP, CSF levels of beta-EP were measured in 15 normally cycling and 15 postmenopausal women. CSF beta-EP levels in post-menopausal women were lower than in fertile women. A positive correlation between plasma E2 and CSF beta-EP level was found in all women. In fertile women CSF beta-EP levels were inversely correlated to plasma gonadotropin levels. These results showed that CSF beta-EP levels differ between fertile and postmenopausal women and are correlated with plasma LH and E2, suggesting a strong linkage between central beta-EP levels and pituitary-gonadal axis hormones.

Endogenous opioids in cerebrospinal fluid of opioid-dependent humans

Endogenous opioid systems may be altered as a consequence of addiction, but evidence to support this idea is meager so far. We obtained 136 cerebrospinal fluid (CSF) samples from 72 opioid addicts during four distinct states: methadone maintenance, detoxification from methadone, opioid antagonist treatment, and drug-free status. CSF endorphins were measured in 86 patient samples using a radioreceptor assay (RRA), and β-endorphin levels were measured in 85 patient samples using a radioimmuno assay (RIA). During detoxification, both RRA fraction I and β-endorphin showed a generally similar pattern of changes. Both were lowest when measured 40–50 hr after the last opioid dose, and both showed an apparent rebound to higher than methadone maintenance values at 60–70 hr following the last dose. During methadone maintenance and drug-free states, the addicts' levels of fraction I RRA endorphins in the CSF were higher than levels found in a normal control group. Fraction II endorphins were also elevated in the addicts who were drug free. In contrast, CSF β-endorphin during both methadone maintenance and drug-free states was lower in the addicts as compared to the normal, drug-naive group. Except for the pattern found during detoxification, there were no consistent changes in endorphin levels across different states of addiction.

Cerebrospinal Fluid Endorphins and the Infant Apnea Syndrome

Cerebrospinal fluid (CSF) beta-endorphin levels were determined in 16 patients with infant apnea syndrome and 34 control patients. A statistically significant difference (P less than or equal to .0001) was found with the infant apnea syndrome patients having beta-endorphin levels of 14.7 +/- 1.2 pmol/L (mean +/- SE) and the controls having levels of 6.9 +/- 0.6 pmol/L (mean +/- SE). To test whether these elevated CSF beta-endorphin levels were the result or the possible cause of the apneas, three patients with infant apnea syndrome and abnormal CSF beta-endorphin levels participated in a study to determine whether a continuous low-dose infusion (10 micrograms/kg/h) of the narcotic antagonist naloxone would reduce the occurrence of apneas and respiratory pauses during all-night polysomnogram recordings. A fourth patient with documented apneas but normal CSF beta-endorphin levels was also studied while on a regimen of naloxone. In the patients with infant apnea syndrome and abnormal CSF beta-endorphin levels, a significant (P less than or equal to .05) reduction in apneas and respiratory pauses occurred during naloxone infusion. There was no change in the occurrence of apneas or respiratory pauses during naloxone infusion in the patient with normal CSF endorphin levels. Abnormal CSF levels of endorphins may play a role in apneas of infancy and may be amenable to therapy with narcotic antagonists.

β-Endorphin levels in the cerebrospinal fluid of male talapoin monkeys in social groups related to dominance status and the luteinizing hormone response to naloxone

β-Endorphin-like immunoreactivity was measured in the cerebrospinal fluid of 20 male talapoin monkeys living in mixed-sex social groups. It was shown that β-endorphin (1–31) was the major immunoreactive peptide; there was no evidence for high molecular weight precursors, or for either N-acetyl or C-shortened metabolites. Dominant males (those at the top of the social hierarchy) had lower levels of β-endorphin than those of intermediate rank; subordinate males had higher levels than either of the other two ranks—about three times those measured in dominants. There were significant negative correlations between β-endorphin in cerebrospinal fluid and both the amount of aggression given and sexual behaviour shown towards females. The response of the hypothalamo-pituitary system to opiate blockade was tested by giving the males naloxone in doses of 0.125, 0.25, 0.5, 1.0 and 5.0 mg/kg and assaying serum levels of luteinizing hormone 20min later. Dominant males released significant amounts of luteinizing hormone at doses of 0.25 and higher; there was no release in either intermediate or subordinate monkeys at any dose. These findings show that an animal's rank in the social group in which it lives is strongly correlated with β-endorphin levels in the cerebrospinal fluid, and with changes in the neuroendocrine response to opiate blockade. Altered opiate neural activity may be responsible for the depressed levels of sexual behaviour and gonadal function observed in monkeys at the bottom of the hierarchy.

Apgar Scores and Cerebrospinal Fluid β-Endorphinlike Immunoreactivity

Sir .—We were interested to read the article in the April issue of AJDC by Laungani and colleagues 1 about the Summary of Cerebrospinal Fluid (CSF) β-Endorphinlike Immunoreactivity Found in the First Three Days of Life CSF β-Endorphin, pg/mL Mean Range SEM First 3 days, asphyxia 22 109 39-184 8.7 First 3 days, no asphyxia 10 34 24-45 2.3 2 We, however, found no correlation between one-minute Apgar scores and β-endorphinlike immunoreactivity from CSF taken in the first 24 hours or three days of life, as found by Dr Laungani. We did, however, find a statistically significant difference between those neonates who

Contrast medium causes the apparent increase in β-endorphin levels in human cerebrospinal fluid following brain stimulation

Levels of β-endorphin immunoreactivity in cerebrospinal fluid were measured in 12 chronic pain patients undergoing the surgical implantation of an electrode into the periventricular gray matter. Cerebrospinal fluid fractions were collected following placement of a cannula into the third ventricle, following injection of metrizamide contrast medium into the ventricles, following implantation of the electrode, and following electrical stimulation. A second set of samples was collected on a non-surgical day before and after stimulation. Levels of β-endorphin immunoreactivity increased significantly from baseline levels to post-electrode implantation in one group of patients, but no significant change was seen following the onset of stimulation. Immunoreactivity increased significantly following metrizamide injection in a second group and was still elevated, in comparison to baseline, following electrode placement, but no increase was seen following the onset of stimulation. Levels of immunoreactive β-endorphin did not increase in either group after stimulation on a post-surgical day, despite consistent reports of pain relief. Addition of metrizamide or a related contrast medium, iothalamate meglumine (Conray) to the β-endorphin radioimmunoassay revealed that both compounds interfered with antigen-antibody binding and also quenched the gamma radiation emitted by iodinated peptide ligands. Due to these combined effects, the contrast media alone produced results similar to those of the β-endorphin standard. Moreover, similar observations were made when contrast media were incorporated into radioimmunoassays for met-enkephalin, dynorphin and cholecystokinin octapeptide. These findings indicate that increased levels of β-endorphin in cerebrospinal fluid are not directly associated with patient report of pain relief following periventricular gray stimulation. This study also suggests that the previously reported association between periventricular gray stimulation and elevated levels of β-endorphin immunoreactivity in ventricular cerebrospinal fluid are artifactual due to the interaction of contrast media with the radioimmunoassay.

Elevated beta-endorphin in cerebrospinal fluid after electrical brain stimulation: artifact of contrast infusion?

Beta-Endorphin-like immunoreactivity in cerebrospinal fluid was assayed in 11 patients receiving electrical stimulation of the brain for chronic pain. Immunoreactivity increased dramatically after contrast ventriculography prior to stimulation. No further elevations were observed after stimulation. The magnitude and time course of elevations were identical after placement of electrodes either in the thalamus or in the periventricular gray matter. These results suggest that previous findings of stimulation-induced elevation of beta-endorphin-like immunoreactivity in cerebrospinal fluid are attributable to an artifact of contrast ventriculography.

Increase of β-endorphin in cerebrospinal fluid after removal of ACTH-secreting pituitary adenomas

β-Endorphin and methionine(met)-enkephalin in cerebrospinal fluid (CSF) were measured before and after removal of an adrenocorticotropic hormone-(ACTH)-secreting adenoma in Cushing's disease by a sensitive radioimmunoassay and a radio-receptor assay, respectively. After tumor resection, the level of ACTH in plasma markedly decreased from 82.6 ± 22.7 pg/ml to 16.7 ± 4.1 pg/ml (mean ± S.E., n = 4). It was found that the level of β-endorphin in CSF significantly increased from 32.0 ± 4.5 pg/ml to 61.8 ± 10.7 pg/ml ( P < 0.05) after tumor resection, while the level of metenkephalin in CSF remained unaltered. This result suggests that hypophysectomy induces an increase of β-endorphin in CSF.

Effect of transcutaneous electrotherapy on CSF β-endorphin content in patients without pain problems

To test the hypothesis of opiate-like peptide release after transcutaneous electrotherapy we measured β-endorphin cerebrospinal fluid (CSF) content in 13 patients without pain problems. The results indicate a time dependent increase of CSF β-endorphin in the group of patients studied. This fact suggests that the analgesic properties of the treatment may be ascribed to an involvement of the endogenous opiates system, independently from the basal clinical conditions of the patients.

INCREASED β-ENDORPHIN BUT NOT MET-ENKEPHALIN LEVELS IN HUMAN CEREBROSPINAL FLUID AFTER ACUPUNCTURE FOR RECURRENT PAIN

Low-frequency electroacupuncture effectively alleviated recurrent pain in 10 patients. Basal levels of β-endorphin and met-enkephalin in the lumbar cerebrospinal fluid (CSF) of these patients were not different from those in pain-free control subjects. After electroacupuncture in the patients with pain CSF β-endorphin levels rose significantly in all subjects, but met-enkephalin levels were unchanged. These results suggest that the analgesia observed after electroacupuncture in patients with recurrent pain may be mediated by the release into the CSF of the endogenous opiate, β-endorphin.