Stress-induced release of brain and pituitary beta-endorphin: major role of endorphins in generation of hyperthermia, not analgesia.

The present paper examines the conjectured causal relationship between the alterations in brain, pituitary and plasma levels of endorphins and the antinociception (analgesia) and hyperthermia elicited by acute stress. A 5-min foot-shock instigated a significant depression in the levels of beta-endorphin immunoreactivity (beta-EI) in both the hypothalamus and periventricular beta-endorphinergic fibre-containing tissue. A large elevation in plasma levels of beta-EI, consisting of about 70% beta-endorphin (beta-EP), and 30% beta-lipotropin (beta-LPH) was associated with a significant reduction in the beta-EI content of both the anterior (AL) and neurointermediate (NIL) lobes of the pituitary. No concomitant changes in the levels of Met-enkephalin immunoreactivity (M-EI) in discrete areas of brain and pituitary were detectable. Application of a high (10 mg/kg) but not a low (1 mg/kg) dose of naloxone, prior to foot-shock, slightly reduced the increase in tail-flick latency evoked by this stress. In contrast, both of these doses strongly and dose-dependently attenuated the accompanying rise in core temperature (Tc). Chronic (approximately 30 day) morphine treatment resulted in a 45% decrease in the NIL content of beta-EI and a clear depression in its basal plasma levels, although a substantial post-stress rise in plasma beta-EI was still found: stress-induced analgesia (SIA) was enhanced, but the concurrent stress-induced hyperthermia (SIH), reduced in morphinized animals. These data demonstrate that stress produces a generalized mobilization of both central and pituitary pools of beta-EI, and indicate that endorphins may play a more important role in the mediation of changes in Tc than in the generation of the concomitant increase in nociceptive threshold, upon activation by stress.

Dynorphin-related immunoreactive peptides in rat brain and pituitary.

Antisera recognizing dynorphin 1-13, but not other opioid peptides with a high avidity, have been generated in rabbits. Using a radioimmunoassay technique levels of dynorphin-immunoreactivity (dyn-ir) have been measured in the brain and pituitary of rats. The concentrations of dyn-ir ranged from a maximum in the intermediate/posterior lobe of the pituitary (about 1200 pmol/g) to a minimum in the cerebellum (about 1 pmol/g) as follows: pituitary intermediate/posterior lobe greater than adenohypophysis greater than hypothalamus greater than hippocampus = striatum = midbrain = thalamus = medulla/pons greater than cortex greater than cerebellum. Gel-filtration of hypothalamic extracts revealed 4 immunoreactive components with apparent molecular weights (MW) of 3500, 2400, 1300 and less than 1000 daltons, respectively. No dyn-ir was found to elute as dynorphin1-13 (MW = 1700). The 2400 and 1300 dalton materials showed opiate-like activity on the guinea-pig ileum longitudinal muscle preparation, indicating that a substantial part of the dyn-ir measured represented biologically active material.

Effects of lesions in the ventral noradrenergic bundle on behavior and response to psychotropic drugs in rats.

Bilateral lesions of the ventral noradrenergic bundle (VB) decreased concentration of noradrenaline within the mesendiencephalon but not in the cortex. Lesioned rats showed increased activity measured in the open field test. Cataloptogenic effects of chlorpromazine and haloperidol were almost completely abolished in VB-lesioned animals. The stereotypy induced by both--amphetamine and apomorphine was, however, unchanged. It is supposed that lesions of the VB lead to increased activity in dopaminergic neurons in the brain.

Effects of lesions of the Locus coeruleus and the ventral noradrenergic bundle on the antinociceptive action of clonidine in rats.

Effects of electrolytic lesions of noradrenergic brain systems on clonidine-induced analgesia were tested in rats by tail-compression method. Bilateral lesions of the locus coereleus decreased clonidine analgesia whilst lesions involving the ventral noradrenergic bundle produced no significant effect. These data demonstrate that antinociceptive effect of clonidine is related to action upon the noradrenergic system of the locus coeruleus.

Audiogenic seizures in rats: relation to noradrenergic neurons of the locus coeruleus.

Bilateral lesions involving the nucleus locus coeruleus produced a substantial decrease in the forebrain noradrenaline concentrations. Lesioned animals showed an increased susceptibility to audiogenic seizures. It is supposed that noradrenergic neurons, belonging to the locus coeruleus, play an inhibitory role in the seizure mechanism.

Studies on the effect of lesions of the ventral noradrenergic tract on the antinociceptive action of morphine.

In rats, lesions were placed in the ventral tegmental noradrenergic tract (VT). In some animals lesions also involved the dorsal tegmental noradrenergic tract (DT). Morphine (Mf) analgesia was examined by the tail compression method 8-9 days after lesions. VT lesions produced no changes in Mf activity, while lesions involving VT + DT produced a partial attenuation of the antinoceptive action of Mf. These results suggest that the ascending NA fibres forming the VT are not essential for the antinoceptive effect of Mf.

Reduced analgesic effects of morphine after bilateral lesions of the locus coeruleus in rats.

Noradnenaline-depleting lesions involving the locus coerulcus markedly reduced morphine analgesia. Rats were tested for analgesia using the tail-compression method. The results indicate that locus coeruleus plays an important role in analgesic action of morphine.

Brain serotonin and epileptic seizures in mice: a pharmacological and biochemical study.

5-Hydroxytryptophan (5-HTP) reduced the intensity of both audiogenic and pentylenetrazol seizures. p-Chlorophenylalanine reduced audiogenic seizure (AGS) susceptibility but failed to change the pentylenetetrazol seizure (PTS). Drugs blocking brain serotonin (5-HT) receptors suppressed AGS but caused no clear effects upon PTS. Pentylenetetraziol-induced shock increased brain 5-hydroxyindoleacetic acid (5hiaa) concentrations and decreased 5-HT levels. Single audiogenic shock decreased the acumulation of 5-HT and 5-HIAA in the brains of mice pretreated with 5-HTP. On the other hand PTS increased the accumulation of 5-HT and 5-HIAA in the brains of mice pretreated with 5-HTP. It is suggested that AGS decrease brain 5-HT turnover whilst PTS cause an opposite effect.

Behavioral effects of neuroleptics, apomorphine and amphetamine after bilateral lesion of the locus coeruleus in rats.

Bilateral lesions of the locus coeruleus (LC) markedly increased susceptibility to the cateleptogenic effects of neuroleptics. The apomorphine-induced stereotypy was enhanced in rats with lesioned LC whilst amphetamine stereotypy was only slightly increased. No changes in locomotor activity have been observed in LC-lesioned rats treated with apomorphine and amphetamine. This data indicates that lesions of the LC produce decreased activity of dopaminergic brain neurons as well as supersensitivity of dopaminergic receptors.

Hexobarbital sleeping time in the rat: effects of isolation and lesions of the locus coeruleus.

Hexobarbital sleeping time was observed in isolated and nonisolated rats with lesioned locus coeruleus (LC). Isolated animals were divided into 2 groups: aggressive (killers) and indifferent (nonkillers). Each group included rats with no lesion, with sham lesion and with LC lesion. Hexobarbital sleeping time was prolonged in nonisolated male, but not female, rats with lesioned LC (7 and 14 days after the lesion). This effect was not observed in animals previously isolated for 3 weeks. These results suggest that the LC plays an important role in the mechanisms of barbiturate sleep, but this effect may be related to the emotionality of animals.

The effects of serotonin injections into the locus coeruleus on ponto geniculo occipital (PGO) waves and cortical EEG pattern in cats.

Reserpine injected iv at 0-8--1-0 mg/kg doses induced continuous ponto-geniculo-occipital (PGO-like) waves in immobilized cats. Both 5-HT and quipazine injected into the locus coeruleus decreased the frequency of reserpine-induced PGO waves and increased cortical synchronization. Suppression of PGO activity persisted for 15--30 min whilst synchronizing effects lasted much longer. Methysergide increased the frequency of PGO activity but caused no clear changes in the EEG pattern.