Vincenzo R. Olgiati

Lack of opiate receptor involvement in centrally induced calcitonin analgesia

Abstract Calcitonin (CT) injected into the brain ventricles (ICV) of conscious rabbits induced an analgesia not reversable by naloxone which could be repeatedly elicited (for 5 days), while tolerance to morphine developed. CT and morphine synergized in vivo when administered ICV in combination. CT did not alter electrically-induced contractions of guinea-pig myenteric plexus-longitudinal muscle and no displace of 3 H-dihydromorphine by CT was observed in brain opiate receptor preparations. We have concluded that the mechanism of centrally induced CT analgesia may be opiate-independent.

The central GABAergic system and control of food intake under different experimental conditions.

Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS). The effect, still evident 24 h after treatment, was not decreased by the GABA receptor-blocker bicuculline. In contrast, intracerebroventricular injections of the GABA receptor-agonist, muscimol, caused an increase in food intake of freely-fed rats that was antagonized by bicuculline. The eating of animals receiving only bicuculline was stimulated in free-feeding and depressed in food-deprived conditions. These opposite results suggest that muscimol binds preferentially to some GABA receptors, probably those within the satiety-controlling areas (i.e. ventromedial hypothalamus), and that bicuculline influences mainly those postsynaptic neurons where GABAergic inputs prevail.These observations and the data from EOS- and GABA-treated rats provide evidence for involvement of GABA neurons in the regulation of feeding behaviour. The balance of the different effects produced in each of these areas by this modulation appears to be a decrease in feeding behaviour.

Calcitonin and prostaglandin system

Abstract It has been repeatedly reported that calcitonin treatment in various diseases with high levels of bone resorption is associated with an antalgic effect, the mechanism of which is far from been clarified. The involvment of prostaglandins and thromboxane in hyperalgesia prompted us to consider the possibility that calcitonin induces its antalgic effect through on interference with prostaglandin and thromboxane synthesis. Guinea pig lung which, perfused with arachidonic acid releases in the perfusate a mixture of thromboxane and prostaglandins, each measurable on a separate smooth muscle tissue (rabbit aorta and rat stomach strip), was used as a test system. Calcitonin added to the perfusion fluid was shown to inhibit the synthesis both of prostaglandins and thromboxane. The concentration of calcitonin (salmon) which decreased the activity of arachidonic acid by 50% (KB) was 0.27 and 0.40 nmoles for prostaglandins and thromboxane respectively. In the experiments carried out using Ca ++ concentration in the perfusion fluid 50% higher than normal (0.28 g/l), calcitonin inhibition of prostaglandins and thromboxane was unchanged (KB = 0.23 and 0.36 nmoles respectively). The reported results by indicating that calcitonin has an influence on cyclooxygenase as indomethacin (used as reference standard) whose it is well known the activity at this level, support the interesting possibility that the antalgic effect consequent to the treatment with the hormone is due, at least in part, to a mechanism involving the prostaglandin synthetase system.

Calcitonin inhibition of physiological and stimulated prolactin secretion in rats

Abstract The administration of salmon Calcitonin (sCT) intravenously (2.5 or 10 μg/kg) or into the lateral cerebral ventricles (2.5 or 25 ng/rat, i.c.v.) of unanaestized male rats induced clearcut decreases in plasma prolactin(PRL) levels. The i.c.v. injection of one of these doses of sCT (25 ng/rat) into rats with median eminence lesions was completely ineffective, while it induced a dramatic decrease in plasma PRL levels of sham-operated rats. Morphine- and heat stress-stimulated PRL levels were also abolished by sCT injection (250 ng/rat i.c.v.). The sCT-induced decrease in PRL levels was completely overcome by haloperidol, a dopamine-receptor blocker. We conclude that sCT may affect PRL secretion via an hypothalamic system, probably involving dopaminergic neurons. The present results indicate that CT, like many others peptides, may affect PRL secretion, directly or indirectly, even though further research is necessary to determine whether this effect has pharmacological or physiological importance.

Presence of opiate receptors on striatal serotoninergic nerve terminals

After degeneration of serotoninergic neurons induced by either transection of the ascending neuronal pathways originating from the nucleus raphe dorsalis or intraventricular 5,6-dihydroxytryptamine administration, the number of binding sites for [3H]D-Ala2, Met5-enkephalinamide was significantly reduced. This decrease in binding sites does not seem to be related to the opiate receptors present on dopaminergic terminals, nor is it due to a simple decrease in serotoninergic neuronal tone, since after p-chlorophenylalanine (100 mg/kg X 4 days) the number of striatal binding sites for the opiate ligand was not diminished. On the other hand, shortly after mechanical interruption of the raphe-striatal serotoninergic fibers, at a time when the metabolic processes are still functioning in the lesioned neurons, morphine still increased the striatal content of 5-hydroxyindoleacetic acid. These results suggest the presence of opiate receptors on striatal serotoninergic terminals, where they may modulate the presynaptic activity of these neurons.

Influence of Brain Histaminergic System on Episodic Growth Hormone Secretion in the Rat

The effects of histamine and amodiaquine (a drug known to inhibit histamine-N-methyltransferase) on pulsatile growth hormone (GH) secretion were determined in unanaesthetized male rats. Intracerebroventricular (i.c.v.) administration of histamine (0.01, 0.05, 0.1 mumol/rat) caused a dose-related suppression of spontaneous pulses of rat GH (rGH) secretion. Amodiaquine (0.16 mumol/rat i.c.v.) also inhibited the pulses, but to a lesser degree. The results, which show the inhibitory effects of both exogenous histamine and increased levels of endogenous histamine on pulsatile rGH secretion, support the hypothesis that the histaminergic system also plays a role in physiological CNS control of rGH secretion.

Role of Catecholamines in Calcitonin-Induced Analgesia

The possibility that the catecholaminergic (CA) system might be involved in calcitonin (CT)-induced analgesia was examined. The administration of the neurotoxin for CA neurons, 6-hydroxydopamine (6-OHDA) significantly reduced salmon CT (sCT) analgesia as measured in rats by the hot-plate test. Pretreatment with an alpha- and beta-blocker (phentolamine and propranolol) was also effective in lowering significantly the activity of sCT. When the two drugs were administered alone, propranolol, but not phentolamine, reduced the analgesic effect of sCT. A more pronounced and long-lasting inhibitory effect on sCT-analgesia was obtained using atenolol (selective beta 1-receptor blocker). The present data support the role of the CA system in sCT-induced analgesic activity.

Histamine Agonist and Antagonist Drugs: Interference with CNS Control of GH Release in Rats

The effects of the administration into the brain ventricle of histamine, selective H1- and H2-receptor agonists and antagonists and chemically similar substances with nonspecific activity on basal and morphine-stimulated growth hormone (GH) secretion in normal male rats were studied. None of the drugs had any significant effect on baseline rat GH levels, but histamine and H1 agonists were able to decrease the rat GH release evoked by morphine. Mepyramine (H1 antagonist) had no consistent effect by itself but was effective in preventing the inhibitory action of 2-methylhistamine (H1 agonist). H2 agonists and antagonists and their chemical analogues were all inhibitory, but by a mechanism which is nonspecific and must be interpreted cautiously. These results confirm the inhibitory effect of histamine on rat GH release and indicate that H1 receptors in the CNS are responsible for this effect.

Effects of the novel antidepressant S-adenosyl-methionine on α1- and β-adrenoceptors in rat brain

Abstract α 1 - and β-adrenoceptors were studied ex vivo in the brains of rats receiving repeated daily treatment with the standard antidepressant imipramine or the atypical antidepressant S-adenosyl-L-methionine (SAM), which has minimal effects on monoamine reuptake or turnover. Consistent with past studies, a decrease in the density of β receptors at three weeks and an increase in the affinity of α 1 receptors for the agonist phenylephrine at one week of treatment was observed with imipramine. By comparison, an increase in the density of β receptors and a decrease in the affinity of α 1 receptors for phenylephrine was observed at one week of treatment with SAM. These changes were no longer apparent at three weeks of treatment. The results suggest that treatment with SAM does lead to changes in adrenergic neurotransmission, but that down regulation of β receptors or increased agonist affinity of α 1 receptors may not be necessary for the production of antidepressant effects.

Failure of somatostatin antiserum to reverse histamine-induced inhibition of pulsatile growth hormone secretion.

We attempted to determine whether the suppression by histamine of spontaneous episodic growth hormone (GH) secretion is mediated by an augmented release of somatostatin (SS). Adult male rats were passively immunized against SS by the injection of a specific goat anti-SS antibody. Plasma GH levels in rats bearing indwelling catheters were measured at 15-min intervals for 4 h. Histamine (0.1 mumol/rat) was administered intracerebroventricularly (i.c.v.) 1 h after the start of the experiment and once an hour for the next 2 h. Anti-SS serum (2 ml) was injected 2 h after the beginning of the experiment to two groups of rats, one given saline i.c.v. and the other histamine i.c.v. Histamine was able to suppress not only spontaneous GH secretion but also the antiserum-stimulated GH release. These data suggest that histamine inhibiton of GH is not mediated by SS but probably by a reduction of GH-releasing hormone or some other stimulatory signal.