Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain.

Biogenic amines (norepinephrine, dopamine, homovanillic acid, serotonin and 5-hyroxyindole acetic acid) were measured by HPLC method in adult F1 generation rats' brain regions (brainstem, hypothalamus, hippocampus, striatum and frontal cortex), whose mothers (P generation) were treated with vitamin A or vitamin D neonatally (hormonal imprinting). Many significant differences were found, related to the maternally untreated controls. In the earlier studied P generation females, vitamin A consistently influenced the serotonerg system (5HIAA), while vitamin D the dopaminerg system (DA or HVA). Vitamin A imprinting always resulted in reduced, while that by vitamin D always in increased tissue levels. In the present case (directly untreated F1 generation) the transgenerational effect was not unidirectional, however biogenic amine tissue levels were strongly disturbed and brain-area dependent. The results call attention to the transgenerational effect of hormonal imprinting in the case of receptor level acting vitamins which are frequently used in the most imprinting-sensitive period (perinatally) of human life and suggests that caution is warranted.

Perinatal alcohol exposure enhances nocistatin levels in adulthood.

In earlier experiments perinatal hormonal imprinting by alcohol decreased the hormone content of immune cells for life. In the present study, both a single day (15% on the third postnatal day) and a long-term treatment schedule of alcohol exposure (3% for 21 days) of dams during lactation significantly (P < 0.01) enhanced endogenous levels of nocistatin in the blood plasma as well as in the cerebrospinal fluid of the offspring, measured in 3-month-old rats. Our data suggest that alcohol consumption during lactation can cause a life-long influence on nocistatin levels in the offspring and most likely modify nocistatin-related functions such as pain tolerance.

[Effect of nociceptin on histamine and serotonin release in the central nervous system]. / A nociceptin hatása a hisztamin és szerotonin kiáramlásra a központi idegrendszerben.

Role in pain sensation of both nociceptin (NC), the bioactive heptadecapeptide sequence of preproorphaninFQ and of histamine has been widely evidenced in the central nervous system (CNS). In the current series of experiments effect of intracerebroventricularly (i.c.v.) administered NC (5.5 nmol/rat) on histamine and serotonin levels in blood plasma, CSF and brain areas (hypothalamus and hippocampus) was studies and compared to the effect of the mast cell degranulator Compound 48/80(100microg/kg, i.c.v.) and the neuroactive peptide Substance P (50nmol/rat, i.c.v.). It was found that all the three compounds increased the histamine level in the CNS, however their activity concerning the mast cell-, and neuronal histamine release is different. NC could release histamine from both the mast cells and the neurons and it decreased CNS serotonin levels. Substance P was found the most potent in increasing CNS histamine levels. Compound 48/80 treatment resulted in elevated histamine levels both in the CNS and blood plasma. It is concluded that the histamine releasing effects of i.c.v. administered NC and SP are limited to the CNS, but in the effect of Compound 48/80 its blood-brain barrier impairing activity is also involved. Data also demonstrate that NC has significant effect on both the histaminergic and serotonergic neurotransmission in the CNS.

[Endogenous nociceptin level in ischemic stroke: connection to serotonin system]. / Endogén nociceptin-szint vizsgálatok ischémiás stroke-ban: a nociceptinerg rendszer kapcsolata a szerotonerg rendszerrel.

Particular role of the heptadecapeptide nociceptin (orphanin FQ), the endogenous agonist of the NOP receptor, has been widely demonstrated in the regulation of pain sensation and anxiety-related behavior. In our best knowledge this is the first study reporting plasma nociceptin levels in 26 acute stroke and 6 transiens ischemic attack (TIA) patients. We have found significantly elevated plasma nociceptin levels in all the three groups of patients studied (stroke influencing the carotis or the lacunar region and TIA). We suggest that elevated plasma nociceptin level is the consequence of stroke as in the group of patients recovered from previous stroke was found similar the control value. Plasma serotonin level was found non-significantly decreased in patients with stroke influencing the lacunar region and TIA patients. However the plasma 5-hydroxy-indoleacetic acid (5HIAA) levels were found significantly elevated in patient groups with stroke influencing both the carotis and the lacunar regions. Data may serve as further evidence for the serotonergic dysregulation in stroke.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Single neonatal treatment with beta-endorphin (hormonal imprinting) extremely enhances nocistatin level of cerebrospinal fluid in adult rats.

In earlier experiments endorphin treatment of newborn rats caused the decrease of brain serotonin content, increasing aggressivity, enhanced sexual activity of females and changes in the binding capacity of uterine estrogen receptors at adult age, however nociceptin content of the cerebrospinal fluid was not changed. In the present experiment neonatal treatment of male and female rats was done with a single dose of 3 microg beta-endorphin and in five months old rats the level of nociceptin antagonist nocistatin was determined by radioimmunoassay in the cerebrospinal fluid. In both genders the amount of nocistatin was one magnitude higher in the endorphin treated groups. There was also a significant difference between the male and female nocistatin level in the treated and non-treated groups alike, with the advantage of females. The results call attention to the possibility of influencing pain-tolerance for life, by the pain-provoked endorphin levels during delivery.

Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma.

AIM: The heptadecapeptide nociceptin alias orphanin FQ is the endogenous agonist of opioid receptor-like1 receptor. It is involved in modulation of pain and cognition. High blood level was reported in patients with acute and chronic pain, and in Wilson disease. An accidental observation led us to investigate nociceptin in hepatocellular carcinoma. METHODS: Plasma nociceptin level was measured by radioimmunoassay, aprotinin was used as protease inhibitor. Hepatocellular carcinoma was diagnosed by laboratory, ultrasound, other imaging, and confirmed by fine needle biopsy. Results were compared to healthy controls and patients with other chronic liver diseases. RESULTS: Although nociceptin levels were elevated in patients with Wilson disease (14.0+/-2.7 pg/mL, n=26), primary biliary cirrhosis (12.1+/-3.2 pg/mL, n=21) and liver cirrhosis (12.8+/-4.0 pg/mL, n=15) compared to the healthy controls (9.2+/-1.8 pg/mL, n=29, P<0.001 for each), in patients with hepatocellular carcinoma a ten-fold increase was found (105.9+/-14.4 pg/mL, n=29, P<0.0001). High plasma levels were found in each hepatocellular carcinoma patient including those with normal alpha fetoprotein and those with pain (104.9+/-14.9 pg/mL, n=12) and without (107.7+/-14.5 pg/mL, n=6). CONCLUSION: A very high nociceptin plasma level seems to be an indicator for hepatocellular carcinoma. Further research is needed to clarify the mechanism and clinical significance of this novel finding.

Rising plasma nociceptin level during development of HCC: a case report.

AIM: Although liver cirrhosis is a predisposing factor for hepatocellular carcinoma (HCC), relatively few reports are available on HCC in primary biliary cirrhosis. High plasma nociceptin (N/OFQ) level has been shown in Wilson disease and in patients with acute and chronic pain. METHODS: We report a follow-up case of HCC, which developed in a patient with primary biliary cirrhosis. The tumor appeared 18 years after the diagnosis of PBC and led to death within two years. Alfa fetoprotein and serum nociceptin levels were monitored before and during the development of HCC. Nociceptin content was also measured in the tumor tissue. RESULTS: The importance and the curiosity of the presented case was the novel finding of the progressive elevation of plasma nociceptin level up to 17-fold (172 pg/mL) above the baseline (9.2+/-1.8 pg/mL), parallel with the elevation of alpha fetoprotein (from 13 ng/mL up to 3 480 ng/mL) during tumor development. Nociceptin content was more than 15-fold higher in the neoplastic tissue (0.16 pg/mg) than that in the tumor-free liver tissue samples (0.01 pg/mg) taken during the autopsy. CONCLUSION: Results are in concordance with our previous observation that a very high plasma nociceptin level may be considered as an indicator for hepatocellular carcinoma.

Impact of single neonatal serotonin treatment (hormonal imprinting) on the brain serotonin content and sexual behavior of adult rats.

Hormonal imprinting takes place perinatally at the first encounter between the developing receptor and its target hormone. As a consequence of imprinting the receptor accomplishes its maturation and reaches the binding capacity characteristic to the adult age. In the excess of target hormone or presence of molecules similar to the target hormone, which are able to bind to the unmatured receptors, faulty imprinting develops with life-long consequences. At present, serotonin was given to neonatal rats and their sexual activity, brain serotonin level and steroid receptor's binding capacity was measured in adult age. Brain serotonin level was significantly reduced in male's striatum and parallel with this, male's sexual activity significantly increased. In other regions of the male brain (prefrontal cortex, hypothalamus, hippocampus) there was a statistically non-significant tendency for a decrease in serotonin level. No significant differences were detected in female brain values, and there was only slight change in female's sexual activity. There was also no change in the binding capacity of thymic glucocorticoid and uterine estrogen receptors. The experiments call attention to the possibility of perinatal imprinting by a neurotransmitter causing changes in brain neurotransmitter level for life, which is manifested in altered sexual activity.

Effect of neonatal beta-endorphin imprinting on sexual behavior and brain serotonin level in adult rats.

A single dose (3 microg) beta-endorphin was administered to newborn female and male rats (hormonal imprinting). In adult age (at 5 months) sexual behavior, steroid hormone binding capacity and brain serotonin content was studied. Females' sexual activity (lordosis quotient) significantly decreased and more animals protested against mounting (ratio of kicking and crying 21/24 vs. 8/24; p < 0.001). Males' sexual activity did not change, however more males were aggressive (4/10 vs. 1/10). Uterine estrogen receptor density significantly increased and affinity decreased. There was no change in the binding capacity of thymic glucocorticoid receptors. In the brain, five regions were studied for serotonin content. There was a gender difference in serotonin level and the intragroup differences were also high. In the endorphin treated males the serotonin level was significantly lower than in the controls. In the endorphin treated females the intragroup scattering has been significantly reduced. Nociceptin content of the cerebrospinal fluid was not changed. The experiments call attention to the possibility of adjustment of sexual and behavioral sphere by the individually different endorphin surge during labor.

Elevated plasma nociceptin level in patients with Wilson disease.

Plasma level of nociceptin, the endogenous agonist of orphanin FQ/ORL1 receptor was found to be significantly elevated in Wilson disease patients (13.98+/-2.44pg/ml, p<0.001, n=20) compared to age-matched healthy controls (9.18+/-1.63pg/ml, n=25). Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutation of the gene ATP7B leading to toxic copper accumulation in the liver and other organs such as brain, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found. It is suggested that elevated plasma nociceptin level found in Wilson disease patients is due to inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N (APN) and endopeptidase 24.15) by the toxic copper deposits in liver and/or brain.

[Peripheral nociceptin levels in Wilson disease]. / Perifériás nociceptin szint Wilson-kórban.

Plasma level of nociceptin, the endogenous agonists of orphaninFQ/OP4 receptor was found to be significantly elevated in Wilson's disease patients (14.87 +/- 2.44 pg/ml +/- SD, p < 0.001, n = 21) compared to age-matched healthy controls (9.18 +/- 1.63 pg/ml +/- SD, n = 25). Wilson's disease is an autosomal recessive disorder caused by mutation of the gene ATP7B leading to toxic copper accumulation mainly in the liver and brain and in other organs such as, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found in Wilson's disease patients. It is suggested that significantly elevated plasma nociceptin level is due to the inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N, endopeptidase 24.15) by the toxic copper levels, as it is known that changing the central Zn atom to Cu results in an approximately 50% inhibition in the activity of these enzymes. The high plasma nociceptin level in Wilson's disease patients may induce significant impairment in nociceptinerg neurotransmission.