Effect of perinatal stress on the biogenic amine neurotransmitter level of the adult rat's brain.

The amount of biogenic amines (dopamine and serotonin) and their metabolites (DOPAC, HVA, 5-HIAA, and 5-HTOL) in five regions of the brain (frontal cortex, hypothalamus, hippocampus, striatum, and brainstem) was studied in the male and female offspring of control and perinatally (48 h before birth or 48 h after birth) food and water deprived dams, when they were three months old, by using HPLC-EC determination. The increase of amine or metabolite level was dominant (19 values increased and 10 decreased related to control). Before-birth stress caused increase in 9 case and only 2 decreased, while in the case of after-birth stress 10 increased and 8 decreased. However, though there is no possibility to decide an exact tendency of direction, the after-birth stress (transmitted by milk) has more expressed effect. Striatum and brainstem were the most touched regions. There was a gender dependence with the dominance of males, except striatum. Blood plasma nociceptin level was also studied and there was a significant elevation in males after pre- and postnatal deprivation, while in females only after postnatal deprivation. The importance of the results in correlation with other stress effects is discussed.

Effect of beta-endorphin imprinting during late pregnancy on the brain serotonin and plasma nocistatin levels of adult male rats.

Female rats were treated with 10 microg of beta-endorphin on the 19th day of pregnancy. Offspring were studied when five months old. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in four brain regions were determined by HPLC-EC and the nocistatin levels of blood plasma using RIA methods. In each brain region studied, the 5-HT levels were highly significantly reduced and that of 5-HIAA in three regions was highly significantly increased. When 5HIAA/5HT ratios, as a measure of serotonin turnover, were calculated, imprinted animals showed extremely high values. Plasma nocistatin level was also significantly elevated. The results call attention to the effect of perinatal endorphin imprinting and its long-term consequences (e.g., setting of aggressiveness, pain tolerance).

Effect of neonatal benzpyrene imprinting on the brain serotonin content and nocistatin level in adult male rats.

Single neonatal treatment (imprinting) with 20 microg benzpyrene results in significant increase of the brain serotonin level in the striatum, while in the other four regions (cortex, brainstem, hippocampus, hypothalamus) when measured in adults can be detected. The nocistatin level of cerebrospinal fluid (CSF) significantly decreases, while there is no change in the plasma nocistatin level. The results call attention to the comprehensive imprinting effect of benzpyrene, which in addition to receptorial, hormonal and sexual behavioral disturbances causes lasting differences in the brain serotonin and nocistatin levels, probably influencing mood and pain tolerance.

Prolonged effect of stress at weaning on the brain serotonin metabolism and sexuality of female rats.

Weanling female rats were stressed (by water and food deprivation for two days) and three months later the following indexes were studied: 5-HT and 5-HIAA levels in five brain regions, blood plasma and cerebrospinal fluid (CSF), sexual activity and nocistatin level of the plasma and CSF. The 5-HIAA content of hypothalamus and brainstem was significantly decreased (in the brainstem with one third) and in the striatum significantly increased. Plasma nocistatin level was significantly increased. Meyerson index and lordosis quotient were similar to control, but the estrus frequency almost doubled in the stressed animals. Much more defense reactions were observed in the stressed females during trials of mating. The results demonstrate that, 1) the perinatal period is not only sensitive to the remote-effects of stress but later could also be stress-sensitive critical periods, and 2) the continuously differentiating (e.g. bone marrow) cells are sensitive to late imprinting by stress, as well as to the brain and the sexual system.

Plasma nociceptin levels are reduced in migraine without aura.

It was demonstrated that both nociceptin, a novel opioid neuropeptide, and its receptor are present in trigeminovascular neurons. In an animal model nociceptin dose-dependently inhibited neurogenic dural vasodilatation. These results suggest that nociceptin may be involved in neurovascular headaches such as migraine. To test this hypothesis, we studied circulating nociceptin levels in 18 patients suffering from migraine without aura and in 24 controls. Headache-free migraineurs had significantly lower nociceptin levels than controls (5.79 +/- 1.82 vs. 9.74 +/- 2.43 pg/ml, P < 0.0001, Student's t-tests). Nociceptin levels were further reduced in six patients studied in the first 3 h of typical migraine attacks (1.04 +/- 0.17 pg/ml). Nociceptin levels correlated with the frequency of attacks in this group of migraineurs. Lower interictal nociceptin levels may contribute to a defective regulation of trigeminovascular neurons in migraineurs which might be important in the pain process of migraine.

Circulating nociceptin levels during the cluster headache period.

The trigeminal innervation of the dura and its vessels has a prominent role in the mechanism of cluster headache. Nociceptin, an opioid neuropeptide, is the endogenous ligand of the OP-4 receptor, with both algesic and analgesic properties depending on the site of action. Nociceptin and its receptor are expressed by trigeminal ganglion cells where they co-localize with calcitonin gene-related peptide, a marker peptide of the trigeminovascular neurones. Nociceptin inhibits neurogenic dural vasodilatation, a phenomenon related to trigeminovascular activation. To explore its possible involvement in cluster headache, we studied circulating levels of nociceptin when attack-free during the cluster period, and also after the termination of the cluster period, using radioimmunoassay. In 14 cluster headache patients nociceptin levels during the cluster period were significantly lower than in age-, and sex-matched controls (4.91 +/- 1.96 vs. 9.58 +/- 2.57 pg/ml, P < 0.01). After the termination of the cluster period nociceptin levels (8.60 +/- 1.47 pg/ml) were not statistically different from controls. Nociceptin levels did not correlate with age, length of disease or episode length. Lower nociceptin levels during the cluster period may result in a defective regulation of trigeminal activity that might not protect sufficiently against the attacks.

Endorphin excess at weaning durably influences sexual activity, uterine estrogen receptor's binding capacity and brain serotonin level of female rats.

Perinatally, the first encounter between the maturing receptor and its target hormone results in hormonal imprinting, which adjusts the binding capacity of the receptor for life. In the presence of an excess of the target hormone or foreign molecules than can be bound by the receptor, faulty imprinting carries life-long consequences. In cytogenic organs, imprinting could also be provoked in other periods of life (late imprinting). Imprinting also durably influences the production of the imprinter and related hormones. In the present study, single beta-endorphin doses was given to three-week old female rats at 3 microg/animal, and the serotonin in five brain regions (frontal cortex, striatum, hippocampus, hypothalamus and brain stem) and uterine estrogen receptor content were determined, thymic glucocorticoid receptor binding capacity was measured, and sexual behavior was tested at five months of age. Brain serotonin levels highly significantly decreased, while sexual activity (Meyerson index and lordosis quotient) increased. At the same time, uterine estrogen receptor affinity decreased. There was no change in receptor binding capacity in the thymus. We will go on to discuss interrelations between the results. The experiments demonstrate that a non-perinatal treatment with a molecule acting at receptor level (late imprinting) can also lastingly influence various indexes in non-cytogenic organs. The results call attention to the possible long-lasting influence of an endorphin surge (caused, for example, by pain) on brain serotonin content and sexual behavior.