Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation.

Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling both neuropathic pain and convulsions in rodents. In this study we compared nefopam to carbamazepine (CBZ), a reference antiepileptic drug (AED), for their ability to protect cerebellar neuronal cultures from neurodegeneration induced by veratridine (VTD). Furthermore, we tested nefopam for protection against both, maximal electroshock-induced seizures (MES), and isoniazid-induced seizures in mice.

Nefopam inhibits calcium influx, cGMP formation, and NMDA receptor-dependent neurotoxicity following activation of voltage sensitive calcium channels.

Nefopam hydrochloride is a potent non sedative benzoxazocine analgesic that possesses a profile distinct from that of anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanism remains unclear. We have investigated the actions of nefopam on voltage sensitive calcium channels and calcium-mediated pathways.

Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.

N-methyl-D-aspartic acid (NMDA) is an agonist at the homonymous receptor implicated in the development of neuronal sensitization and its behavioral correlates. An effective modulation of the NMDA effects, achieved also by uncompetitive antagonists, could contribute to controlling pain symptoms in several neuropathic syndromes. Because nefopam is a known analgesic derivative of orphenadrine and of its congener diphenhydramine, both uncompetitive NMDA receptor antagonists, we tested the effect of nefopam on the developing pain and neuronal anomalies in an animal model of chronic pain with NMDA receptor involvement.

Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity.

Nefopam hyghochloride is a potent analgesic compound commercialized in most Western Europe for 20 years, which possesses a profile distinct from that of opioids or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanisms remain unclear. While, nefopam structure resembles that of orphenadrine, an uncompetitive NMDA receptor antagonist, here we report that differently from orphenadrine, nefopam (100 microM) failed to protect cultured cerebellar neurons from excitotoxicity following direct exposure of neurons to glutamate.

Novel effect of nefopam preventing cGMP increase, oxygen radical formation and neuronal death induced by veratridine.

Nefopam hydrochloride is a potent analgesic compound that possesses a profile distinct from that of opiods or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanisms remain unclear. Here we have used cultured cerebellar neurons to test the hypothesis that nefopam may modulate voltage sensitive sodium channel (VSSC) activity.

Biochemical evidence of functional interaction between mu- and delta-opioid receptors in SK-N-BE neuroblastoma cell line.

Radioligand binding assays and functional experiments revealed that the SK-N-BE neuroblastoma cell line expresses a similar ratio of mu- and delta-opioid receptors, both negatively coupled to adenylyl cyclase through pertussis toxin-sensitive G proteins. Our findings also indicate that some functional interaction occurred between the two opioid subtypes; in fact, long-term exposure to [D-Ala2-N-methyl-Phe4-Gly-ol5]enkephalin (DAMGO), a mu-selective agonist, sensitized the functional response of the delta-selective agonist but not vice versa. It is interesting that in acute interaction experiments, we observed a shift to the right of the concentration-effect curve of either DAMGO or [D-Pen2,5]enkephalin (DPDPE), a delta-selective agonist, as a result of DPDPE or DAMGO administration, respectively.

Behavioral and biochemical evidence of opioidergic involvement in cocaine sensitization.

Chronic administration of cocaine produces sensitization to its behavioral effects in humans and experimental animals. In the present study, rats treated with cocaine (10 mg/kg, i.p.

Cholera toxin antagonizes morphine-induced catalepsy through a cyclic AMP-independent mechanism.

We studied the effect of intracerebroventricular pretreatment with pertussis toxin and cholera toxin on morphine catalepsy in rats. Pertussis toxin (1 micrograms/rat, two, three and six days before) did not affect catalepsy evoked by central morphine. Cholera toxin (1 micrograms/rat) did not affect morphine catalepsy after 24 h and 48 h, but significantly reduced it (about 60%) after three and five days.

Role of opiates in striatal D-1 dopamine receptor supersensitivity induced by chronic L-dopa treatment.

Repeated administration of L-dihydroxyphenylalanine (L-dopa) to rats lesioned with monolateral intranigral injections of 6-hydroxydopamine counteracted the increased density of striatal [3H]spiroperidol binding sites induced by the lesion. On the contrary, the treatment with L-DOPA further enhanced the hypersensitivity of adenylate cyclase to dopamine stimulation that follows striatal denervation. In addition, the apomorphine-induced rotations were strongly potentiated.

Pertussis toxin inhibits morphine analgesia and prevents opiate dependence.

Six days after intracerebroventricular pretreatment of rats with pertussis toxin (PTX 0.5 microgram/rat) there was a marked decrease in the antinociceptive effect of morphine, regardless of the route of opioid administration (into the periaqueductal gray matter, intrathecally or intraperitoneally) or the analgesic test used (tail flick and jaw opening reflex). PTX pretreatment also partially attenuated the naloxone-precipitated withdrawal syndrome in morphine-dependent rats, significantly reducing teeth chattering, rearing and grooming.

Cross-talk between different intracellular signalling pathways in the rat hippocampus.

The activation of alpha 1-adrenergic receptors in rat hippocampal slices enhances polyphosphoinositide (PPI) breakdown and cyclicAMP (cAMP) accumulation. The latter effect is antagonized by different protein kinase C (PKC) inhibitors and mimicked by a diacylglycerol (DAG) analogue, 1,2-diolein, which activates PKC, suggesting that cAMP synthesis is indirectly affected by alpha 1-adrenoceptors through the stimulated generation of DAG upon PPI hydrolysis. Furthermore the elevation of hippocampal cAMP decreases the ability of alpha 1-receptor agonists to enhance PPI breakdown.

Role of dopamine in manganese neurotoxicity.

Manganese chloride increased cell mortality when added to human fibroblast cultures. The toxicity of the metal was greatly enhanced by dopamine; this effect was antagonized by the presence in the culture medium of catalase and superoxide dismutase enzymes. Manganese chloride also caused a marked decrease of striatal dopamine concentrations when infused into rat substantia nigra.

Effect of aspirin on serotonin and met-enkephalin in brain: correlation with the antinociceptive activity of the drug.

Intravenous administration of acetyl salicylate of lysine, a soluble salt of aspirin, reduced in rats the firing discharge of thalamic neurones, evoked by noxious stimuli. Concomitantly, concentrations of 5-hydroxyindole acetic acid increased, while those of met-enkephalin-like immuno-reactive derivatives were decreased in several areas of the brain. Similar electrophysiological and biochemical responses were obtained by administering tryptophan or 5-hydroxytryptophan plus carbidopa.

Effects of the desensitization by morphine of the opiate-dependent adenylate cyclase system in the rat striatum on the activity of the inhibitory regulatory G protein.

Opiates act through a specific receptor to inhibit the striatal adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4,6.1.1] and stimulate a high-affinity GTPase (EC 3.

Manganese neurotoxicity: effects of L-DOPA and pargyline treatments.

Single, monolateral injection into rat substantia nigra of manganese chloride produced within two weeks from its administration a loss of dopamine in the striatum ipsilateral to the injected side. The effect was dose-dependent and was not extended to serotoninergic terminals present in this brain area, whose content in serotonin and 5-hydroxyindoleacetic acid was not affected. When L-DOPA + carbidopa or pargyline were given to these animals the decrease of striatal dopamine was more marked.

Differential effect of repeated treatment with L-dopa on dopamine-D1 or -D2 receptors.

Unilateral degeneration of the nigro-striatal dopaminergic pathway with 6-hydroxydopamine induced contralateral rotations to apomorphine injection, increased [3H]-spiroperidol binding and enhanced sensitivity of adenylate cyclase to dopamine stimulation in lesioned striata. Prolonged L-DOPA administration counteracted the increased density of [3H]-spiroperidol binding sites but further enhanced the hypersensitivity of adenylate cyclase to dopamine. Also apomorphine-induced contralateral rotations were potentiated.

Dopamine receptor changes in response to prolonged treatment with L-dopa.

Unilateral lesions of the nigro-striatal dopamine (DA) pathway induced contralateral rotations to apomorphine, increased (3H)-spiroperidol binding and enhanced the sensitivity of striatal adenylate cyclase to DA stimulation. Prolonged L-dopa administration counteracted the increased density of (3H)-spiroperidol binding sites but further enhanced the hypersensitivity of adenylate cyclase to DA and decreased the inhibitory effect of opiates on this enzyme. The apomorphine-induced contralateral rotations were also strongly potentiated.

Opiate and dopamine stimulate different GTPase in striatum: evidence for distinct modulatory mechanisms of adenylate cyclase.

Previous studies demonstrated that opiate inhibition of adenylate cyclase (AC) in striatal membranes is related to an opiate-stimulated GTPase with a low Km. Dopamine (DA) also dose-dependently activates a high affinity GTPase, with a pattern of stimulation and a receptor selectivity (D1 type) similar to those observed in DA activation of striatal AC. Moreover, the DA- and the opiate-sensitive GTPase activities have different sensitivities to agents that affect the inhibition of AC, such as Na+ and N-ethylmaleimide (NEM), or the stimulation, such as cholera toxin (CTX).

Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine.

Repeated administration of fenfluramine leads to a rapid and progressive loss of its effectiveness in reducing food intake. The animals tolerant to the anorectic effect of fenfluramine had markedly low basal hypothalamic serotonin (5-HT) levels. In this brain area the levels of [Met5]enkephalin-like immunoreactive material were, on the contrary, significantly higher in fenfluramine-tolerant animals than in controls.

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.

Opiate tolerance and dependence is associated with a decreased activity of GTPase in rat striatal membranes.

In vitro addition of opiates to rat striatal membranes significantly stimulated a low Km GTPase activity. The opioid peptide (D-Ala2, Met5) enkephalinamide was ten folds more active than morphine to elicit the effect while the kappa agonist ethylketocyclazocine was almost inactive. Opiate stimulation was antagonized by naloxone, indicating that specific opiate receptors were involved.

Interactions between serotonergic and enkephalinergic neurons in rat striatum and hypothalamus.

We report evidence for an interaction between serotonergic and enkephalinergic neurons in rat striatum and hypothalamus. The administration of drugs such as p-chlorophenylalanine (PCPA), 5,6-dihydroxytryptamine (5,6-DHT) and fenfluramine that lower the striatal and hypothalamic serotonin (5-HT) content caused an increase in Met-enkephalin-like immunoreactive material (ME-IR) in these brain areas. Moreover, chronic treatment with PCPA induced an increase in the number of striatal [3H][D]Ala2,Met5]enkephalinamide binding sites.