F. Zambotti

MODIFICATION OF THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY CENTRALLY ADMINISTERED DIAZEPAM AND MIDAZOLAM

1 Intracerebroventricular administration of diazepam or midazolam decreased the antinociceptive effect of morphine in rats as measured by the ‘tail flick’ method. 2 Midazolam, injected into the periaqueductal grey matter (PAG) antagonized the analgesic effect of morphine. The action of midazolam was partially reversed by bicuculline. 3 These findings support the view that the effect of benzodiazepines on morphine antinociception may be mediated through γ‐aminobutyric acid receptors.

Periaqueductal gray matter involvement in the muscimol-induced decrease of morphine antinociception

SummaryMicroinjections of muscimol, a GABA receptor agonist, into the periaqueductal gray matter (PAG) counteracted the antinociceptive effect of morphine in rats, as measured by the “tail-flick” method. Muscimols effect was partially reversed by bicuculline.

Muscimol antagonism of morphine analgesia in rats.

1 Muscimol, a γ‐aminobutyric acid (GABA) receptor agonist, when injected intraventricularly antagonizes the antinociceptive effect of morphine given either subcutaneously or intraventricularly. The antagonistic effect of muscimol on morphine analgesia appears to be linearly related. 2 This finding provides support for the view that a GABA‐ergic system is involved in morphine analgesia.

Effects of some GABA-mimetic drugs on the antinociceptive activity of morphine and ?-endorphin in rats

SummaryIntracerebroventricular administration of muscimol, a potent GABA-receptor agonist, counteracted the antinociceptive effect of morphine or β-endorphin in rats as measured by the “tail flick” method. Muscimols activity was reversed by bicuculline. Isoguvacine, another GABA agonist, as well as nipecotic acid and guvacine, two inhibitors of neuronal and glial uptake of GABA, also antagonized morphines antinociceptive effect. A role of the central GABA-ergic system in mediating opiate antinociception is proposed.

Stimulatory Role for Brain Serotoninergic System on Prolactin Secretion in the Male Rat

Summary Systemic administration of parachlorophenylalanine (PCPA, 100 mg/ kg sc on alternate days x two times), a blocker of serotonin (5-HT) synthesis, considerably decreased brain 5-HT and plasma prolactin (PRL) levels in young male rats. Intraventricular (IVT) administration of 5,7-dihydroxytryptamine (5,7-DHT, 200 μg/20 μl), a neurotoxic drug which destroys 5-HT nerve terminals, induced, 3, 12, and 30 days after treatment, a marked depletion of brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and considerably reduced plasma PRL levels at each time interval. Feeding of rats for up to 4 days with a tryptophan (TP)-deficient diet, caused a depletion of brain 5-HT and 5-HIAA contents and did not modify plasma PRL levels. Addition of TP (2 g/kg of diet) to the TP-deficient diet resulted in increased brain 5-HT and 5-HIAA contents and significantly increased PRL levels. These data provide evidence for the role of the 5-HT system in the maintenance of tonic PRL secretion. We are grateful for the technical assistance of Miss Tecla Ciapparelli and Mr. Giuseppe Tavasci, and to Miss Delia Deriu for skillful secretarial help. Dr. H. G. Baumgarten kindly supplied 5,7-DHT. The reagents for the rat PRL radioimmunoassay were a gift of the Rat Pituitary Hormone Distribution Program of the National Institute of Arthritis, Metabolism, and Digestive Diseases.

Behavioural effects of a new non-phenylethylamine anorexigenic agent : Mazindol

Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with increases in locomotor activity and body temperature. Mazindol also induces stereotyped behaviour and, if injected into rats with unilateral nigro-striatal lesions, causes turning towards the lesioned side. Mazindol-induced anorexia is antagonized by pretreatment with alpha-methyl-p-tyrosine or pimozide. Pimozide pretreatment prevents the rotation induced by Mazindol in rats with unilateral nigro-striatal lesions. The involvement of dopamine in the mechanism whereby Mazindol elicits anorexia and turning behaviour is discussed.

Effects of diazepam on nociception in rats

SummaryAcute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg−1 day−1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency.Diazepam injected intracerebroventricularly (1, 5, 20 μg/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 μg/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency.These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

EFFECTS OF MAZINDOL, A NON‐PHENYLETHYLAMINE ANOREXIGENIC AGENT, ON BIOGENIC AMINE LEVELS AND TURNOVER RATE

1 Mazindol is a new anorexigenic agent which possesses a different chemical structure from that of phenylethylamines, but shows a pharmacological profile similar to that of (+)‐amphetamine. 2 Mazindol neither altered whole brain monoamine levels (noradrenaline (NA), dopamine, 5‐hydroxytryptamine (5‐HT)) nor changed NA levels in the hypothalamus or dopamine levels in the caudate nucleus. 3 Mazindol enhanced dopamine turnover rate in the caudate nucleus, as shown by the increased rate of dopamine decline after blockade of catecholamine synthesis by α‐methyl‐p‐tyrosine and decreased the conversion index of [3H]‐tyrosine into brain NA. 4 Mazindol administration did not modify pargyline‐induced decline of 5‐hydroxyindoleacetic acid suggesting that 5‐HT turnover is not altered by this drug.

The effect of gabaergic agents on opiate analgesia

Summary The present study shows that the intraventricular injection of muscimol (250 ng/ventricle), a potent GABA receptor agonist, strongly antagonized morphine and β-endorphin analgesia. Furthermore, isoguvacine, a compound structurally related to muscimol, and nipecotic acid and guvacine, inhibitors of GABA uptake, administered intraventricularly markedly attenuated the analgesic effect of morphine. These results further substantiate that the GABAergic system is involved in morphine analgesia. A possible mechanism of action is discussed.

Mazindol and amphetamine as inhibitors of the uptake and releasers of 3H-dopamine by rat striatal synaptosomes

SummaryThe effects of mazindol, amphetamine and fentluramine on uptake and release of 3H-DA by synaptosomes were studied in different systems.In in vitro incubations of 3H-DA with synaptosomes isolated from the caudate nucleus of the rat, mazindol inhibited the uptake of the radioactivity more potently than did amphetamine.When the synaptosomes were isolated from the caudate nuclei of rats treated in vivo with either mazindol or amphetamine, the uptake of 3H-DA during in vitro incubation was lower with synaptosomes of amphetamine-treated rats than with those of mazindol-treated rats.When synaptosomes of untreated rats were prelabelled with 3H-DA and incubated in the presence of amphetamine or of mazindol, amphetamine caused a greater releaseoof radioactivity than did mazindol.Fenfluramine was without activity in all these systems.In spite of the quantitative differences, both amphetamine and mazindol appear to have similar effects on uptake and release of dopamine, and this may account for their analogous pharmacological profile.