Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5-hydroxytryptamine involvement in muscimol's effect.

The effect of morphine (3 mg kg-1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR). The levels of 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and striatum of muscimol-injected animals. Muscimol injections in the DR reduced 5-HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5-HIAA levels was found. Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR. An injection of 5,7-dihydroxytryptamine (6 micrograms in 3 microliter) in the DR did not change the effect of morphine or muscimol. These findings indicate that muscimol-sensitive neurones in the DR, which are probably not 5-hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol-sensitive neurones involved in this effect of morphine do not seem to exist in the MR.

Evidence that 5-hydroxytryptamine in the forebrain is involved in naloxone-precipitated jumping in morphine-dependent rats.

A withdrawal syndrome was precipitated by naloxone in morphine-dependent rats injected with 5,7-dihydroxytryptamine (5,7-DHT) in the ventromedial tegmentum (VMT) at the level of the nucleus interpeduncularis. 5,7-DHT, which markedly depleted 5-hydroxytryptamine (5-HT) in the forebrain but not in the brainstem, significantly reduced jumping in abstinent rats with no significant effect on other withdrawal signs. The effect of morphine 10 mg kg-1 on responses on the hot plate was unchanged in 5,7-DHT-treated rats. The findings suggest that 5-HT in the forebrain is selectively involved in the jumping of morphine-abstinent rats.

Methysergide and metergoline reduce morphine analgesia with no effect on the development of tolerance in rats.

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle + morphine or serotonin antagonists + morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.

Evidence of a preferential role of brain serotonin in the mechanisms leading to naloxone-precipitated compulsive jumping in morphine-dependent rats.

Various drugs acting on brain serotonin or catecholamines were administered concurrently with morphine during the development of dependence or before naloxone-precipitated withdrawal syndrome. Of the various drugs only cyproheptadine, a serotonin antagonist, and piribedil, a dopamine agonist, reduced the frequency of jumping (but not of diarrhea or ptosis) when administered with morphine during development of dependence. When administered before naloxone, d-fenfluramine, a serotonin releaser, markedly reduced jumping, but not diarrhea and ptosis, and clonidine blocked these latter signs without affecting the frequency of jumping. Of the other drugs examined only phenoxybenzamine reduced diarrhea in morphine-abstinent rats. It is suggested that serotonin is involved in the mechanisms which lead to compulsive jumping during naloxone-precipitated withdrawal, whereas adrenergic sites on which clonidine acts are mainly involved in the expression of signs, such as ptosis and diarrhea. No clear evidence was obtained of a role for dopamine in the withdrawal signs studied.

Differences in the effects of d-fenfluramine and morphine on various responses of rats to painful stimuli.

The effects of d-fenfluramine and morphine on various nociceptive responses of rats were investigated. Unlike morphine, which inhibited all the responses examined, d-fenfluramine inhibited jumping and paw licking of rats on a hot plate, but did not increase the latency of tail withdrawal from hot water. The effects of d-fenfluramine on both responses on the hot plate were prevented by pretreatment with metergoline, a serotonin antagonist, whereas this pretreatment only reduced the effect of morphine on paw licking. The inhibition of tail withdrawal by morphine was also significantly reduced by metergoline treatment. The results confirm previous findings suggesting a role of serotonin in the mechanism by which morphine inhibits some nociceptive responses in rats. They also show that d-fenfluramine, a selective releaser and uptake inhibitor of serotonin at nerve endings, does not completely reproduce the antinociceptive effects of morphine in this species.

Drugs: guide and caveats to explanatory and descriptive approaches--II. Drugs in psychiatric research.

Over the last two decades animal models, mediators and drugs have produced a mass of experimental data difficult to relate to the epidemiological and clinical side of psychiatric disorders. Antidepressant drugs are chosen as a model case to describe a more general scene: far from being a specific tool--a guide--in a complex situation, these drugs are acquiring a role which must be interpreted with caution (a caveat), in view of ample clinical evidence of responders to placebo, responders to any drugs, responders to many drugs, etc. Studies of biochemical descriptors of drug action as a marker of the disease and its outcome have drawn puzzling pictures, often contradictory and unstable in terms of the populations to whom they can be applied. Controlled clinical trials with antidepressant drugs over the last ten years have persisted in looking for short-term pharmacological effects rather than the medium- or long-term impact of medication in large populations. To establish a positive role for antidepressant drugs, they must be studied in a "natural" context where depressed patients are treated with all necessary follow-up.

Localization of GABAA and GABAB receptor subtypes on serotonergic neurons.

The effect of selective destruction of serotonin (5-HT)-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT) on [3H] muscimol and (-)-[3H]baclofen binding was investigated in various rat brain regions. Ten days after intracerebroventricular 5,7-DHT, serotonin levels and [3H]imipramine binding were markedly decreased. 5,7-DHT reduced [3H]muscimol binding only in the mesencephalon, and (-)-[3H]baclofen binding was unmodified in all the areas considered. These results suggest that except in the mesencephalon GABA receptors may not be localized on serotonergic nerve terminals.

Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus.

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 micrograms/0.5 microliter in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 micrograms/0.5 microliter). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.

The effect of different lesions of the median raphe on morphine analgesia.

The effect of different manipulations of the nucleus medianus raphe (MR) on morphine analgesia was investigated in rats using the tail-immersion test. Electrolytic lesions of this structure antagonized morphine analgesia, while injections of 5,7-dihydroxytryptamine (to destroy serotonergic neurons) or ibotenic acid (to destroy cell bodies) in the medianus raphe did not alter the effect of morphine. Injection of naloxone (0.5 and 0.1 micrograms) in the MR antagonized morphine analgesia. These results suggest the importance of this structure for morphine analgesia in this test, although the substrates within the nucleus that mediate this action are still unknown.

Different effects of zimelidine on the reinforcing properties of d-amphetamine and morphine on conditioned place preference in rats.

The possibility that serotoninergic mechanisms control the reinforcing properties of d-amphetamine and morphine was investigated in rats, using zimelidine, a potent and selective serotonin uptake blocker and the conditioned place preference test design. Zimelidine dihydrochloride 20 mg/kg did not cause place aversion and did not modify the place preference induced by 5 mg/kg morphine hydrochloride. Place preference induced by 5 mg/kg d-amphetamine sulphate was completely blocked by pretreatment with zimelidine. The results suggest that the reinforcing properties of d-amphetamine, but not of opioid agonists, may be reduced by agents which increase serotonin transmission in the brain.

Evidence of the involvement of dopamine in the analgesic effect of nefopam.

The involvement of brain monoamines in the mechanism of action of nefopam, a new analgesic, was investigated in rats. The study was designed to evaluate the effect of various means of impairing monoaminergic transmission on nefopam analgesia as measured with the hot plate method. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive action of nefopam (40 mg/kg), indicating that the interaction of this drug with the monoaminergic systems is important for its effects. A role for serotonin (5-HT) or norepinephrine (NE) was ruled out by the fact that selective depletion of 5-HT (using 5,7-dihydroxytryptamine) or NE (using DSP-4 or FLA-63) did not affect nefopam analgesia. A significant reduction of the effect of nefopam was found in rats pretreated with 6-hydroxydopamine (6-OHDA). Also 6-OHDA plus desipramine, which selectively depleted brain DA, markedly reduced the antinociceptive effect of nefopam. The data strongly suggest that a critical dopaminergic synapse is involved in the mechanism by which nefopam inhibits nociceptive responses in rats.

Studies on the separate roles of forebrain and spinal serotonin in morphine analgesia.

5,7-Dihydroxytryptamine (5,7-DHT) injections in the ventromedial tegmentum (VMT) at the level of nucleus interpeduncularis or in the ventral raphe area (VR) of the medulla oblongata were used to study the separate roles of forebrain and spinal 5-HT in the antinociceptive effect of morphine in rats. 5,7-DHT injections in the VMT, which caused marked, selective depletion of forebrain 5-HT, did not modify the effect of morphine in the hot plate and tail immersion tests. Direct injection of 5,7-DHT into the nucleus raphe medianus also failed to modify the effect of morphine in the two tests used to measure nociceptive responses. The effect of morphine was significantly reduced 30 min after injection to rats depleted of spinal 5-HT by 5,7-DHT injected in the VR but the areas under the curves between vehicle and 5,7-DHT treated animals were not significantly different. The data show that the integrity of 5-HT neurons in the forebrain is not necessary for the antinociceptive effect of morphine and a substantial amount of this effect is still present in rats with marked depletion of spinal 5-HT.

The effect of intracerebroventricular 5,7-dihydroxytryptamine on morphine analgesia is time-dependent.

The analgesic effect of morphine in the tail immersion test was studied in rats three and ten days after intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT) given to selectively destroy serotonergic neurons. Morphine analgesia was reduced three but not ten days after the neurotoxin. Ten days after 5,7-DHT, the inhibiting effect of metergoline, a serotonin antagonist, on morphine analgesia was still present, suggesting that functional recovery of the serotonergic system may partly explain the different results.

Evidence that drugs increasing 5-hydroxytryptamine transmission block jumping but not wet dog shakes in morphine-abstinent rats: a comparison with clonidine.

(+)-Fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and uptake blocker, m-chlorophenylpiperazine (CPP), a 5-HT receptor agonist, and clonidine, an agonist at adrenoceptors, were studied for their ability to modify jumping and wet dog shakes in morphine abstinent rats. (+)-Fenfluramine and CPP blocked jumping with no effect on wet dog shakes whereas the reverse was true for clonidine. The results further show that 5-HT mechanisms are preferentially involved in the expression of jumping in morphine-abstinent rats.

Review on sobrerol as a muco-modifying drug: experimental data and clinical findings in hypersecretory bronchopulmonary diseases.

Sobrerol is an agent with a terpenic structure used to modify mucus characteristics in patients with hypersecretory bronchopulmonary diseases and this review is aimed at listing and discussing all the scientific evidence on this drug. All the toxicological findings testify its excellent tolerability and very low toxicity. In the pharmacological section of the review the effects of sobrerol on mucus production and its characteristics are discussed together with its effect on experimental models. A number of open clinical trials suggesting a therapeutic potential activity of the drug is examined together with a series of randomized double-blind clinical trials confirming its efficacy in relieving obstructive symptoms in chronic bronchitic patients.

Preliminary data on the action of nesosteine, a mucomodifying drug, on mucociliary transport.

Nesosteine, which is active on airway secretions, has been studied by assessment of the mucociliary clearance of the frog palate. Sputum was collected from patients admitted to hospital with acute exacerbations of chronic bronchitis with mucous expectoration. The relative speed of transport was measured for each patient before and after oral administration of 600 mg/day nesosteine. A significant increase in the mucus transport rate was found at the end of treatment.

[Control of the progress of arteriosclerosis in high risk subjects treated with mesoglycan. Measuring the intima media]. / Controllo della progressione dell'arteriosclerosi in soggetti ad alto rischio trattati con mesoglicano. Misurazione dell'intima-media.

BACKGROUND: Noninvasive ultrasonic biopsy (UB) can be used to classify arteriosclerotic lesions and their progression in the carotid and femoral bifurcation. Also the evaluation of intima-media thickness (IMT) is useful to quantify the progression of early arteriosclerosis. METHODS: Two randomly selected groups of asymptomatic subjects were included in a 18 month, open study. One group was treated with oral mesoglycan (200 mg/day) and one group was followed-up as control. The two groups were comparable for age and sex distribution. RESULTS: The average UB score was 14.4 +/- 5 in the treatment group and 14.3 +/- 8 in the control group. After 18 months the UB score was 15.7 +/- 4 in the treatment and 16.2 +/- 6 in the control group. The average increase in IMT in 18 months in the treatment group was 0.016 mm equivalent to 0.0106 mm per year. In the control group the average increase was 0.119 equivalent to 0.0793 per year. Therefore the increase in IMT was 7.48 times greater in the control group. These differences were significant (p < 0.05). Two drop-outs were recorded in the treatment group and 1 in the control group. CONCLUSIONS: In conclusion IMT measurements showed a decreased level of IMT progression in subjects under mesoglycan treatment. These results need to be confirmed by a larger randomised study.