RESUMEN
A seizure-protecting effect of the delta-sleep-inducing peptide (DSIP) and its analogues was revealed. An intensive sorption of H3 tryptophan occurred under the effect of the DSIP and its analogues. The data obtained suggests that the serotoninergic system plays no important part in the seizure-protecting effect.
Asunto(s)
Anticonvulsivantes/farmacología , Péptido Inductor del Sueño Delta/análogos & derivados , Péptido Inductor del Sueño Delta/farmacología , Receptores de Serotonina/efectos de los fármacos , Animales , Anticonvulsivantes/administración & dosificación , Convulsivantes , Péptido Inductor del Sueño Delta/administración & dosificación , Evaluación Preclínica de Medicamentos , Epilepsia Generalizada/inducido químicamente , Epilepsia Generalizada/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Ácido Kaínico , Masculino , Picrotoxina , Ratas , Ratas Wistar , Receptores de Serotonina/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiología , Tritio , Triptófano/metabolismoRESUMEN
Statistical analysis of the interpeak latencies of brainstem auditory evoked potentials (BAEP) shows that a delayed IPL I-V is a very sensitive indicator for an early diagnosis of Wernicke's encephalopathy. In cases of uncomplicated delirium tremens no significant deviations of BAEP were found.
Asunto(s)
Alcoholismo/complicaciones , Tronco Encefálico/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Encefalopatía de Wernicke/diagnóstico , Estimulación Acústica , Delirio por Abstinencia Alcohólica/diagnóstico , Delirio por Abstinencia Alcohólica/fisiopatología , Alcoholismo/fisiopatología , Electroencefalografía , Humanos , Conducción Nerviosa/fisiología , Estudios Prospectivos , Psicosis Alcohólicas/diagnóstico , Psicosis Alcohólicas/fisiopatología , Tiempo de Reacción/fisiología , Procesamiento de Señales Asistido por Computador , Encefalopatía de Wernicke/fisiopatologíaRESUMEN
The necessity of testing psychoactive drugs in awake freely moving animals has led to the development of a telemetry-based system which enables the pharmacologist to follow centrally active molecules in their time- and dose-dependent effects on electric brain activity in terms of changes in spectral power density of extracellularly recorded field potentials (tele-EEG). This report describes the effect of three analgesics with respect to bioelectric changes in frontal cortex, thalamus, striatum and reticular formation. Two opiate drugs, morphine and tramadol, behaved very similarly despite a tenfold difference in dosage, whereas flupirtine, a nonopiate analgesic, changed the frequency content of the EEG signals in an entirely different manner. The frequency pattern produced by the opiates closely resembles that of centrally acting serotonin uptake inhibitors and thus is consistent with the view of a serotonergic prevalence of neurochemical interactions within the recorded brain areas. In contrast, the action of flupirtine obviously can be attributed to a clonidine-like effect on noradrenergic alpha 2-receptors. The results are discussed with respect to already known influences of these drugs on indoleaminergic and catecholaminergic transmission.
Asunto(s)
Aminopiridinas/farmacología , Analgésicos/farmacología , Encéfalo/efectos de los fármacos , Ciclohexanoles/farmacología , Electroencefalografía , Morfina/farmacología , Tramadol/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas F344 , Receptores Adrenérgicos/efectos de los fármacos , Formación Reticular/efectos de los fármacos , Procesamiento de Señales Asistido por Computador , Tálamo/efectos de los fármacosRESUMEN
The antinociceptive activity of flupirtine was measured in various test procedures predictive of analgesic activity. In the electrostimulated pain test in mice the oral ED50 for flupirtine was 25.7 mg/kg p.o. Thus, flupirtine was approximately 31.7 times more potent than paracetamol (ED50: 814 mg/kg p.o.) and as potent as pentazocine (ED50: 38.5 mg/kg p.o.). Morphine (ED50: 16.8 mg/kg p.o.) was 1.5 times and buprenorphine (ED50: 2.6 mg/kg p.o.) 9.9 times more potent than flupirtine. In the hot plate test (mice) flupirtine (ED50: 32 mg/kg p.o.) was approximately half as potent as morphine (ED50: 15.5 mg/kg p.o.). The oral and intravenous antinociceptive activity (ED50) of flupirtine in the electrical tooth pulp stimulation test in conscious dogs was 3.5 mg/kg p.o. and 0.7 mg/kg i.v. which was similar to that of pentazocine (ED50: 4.2 mg/kg p.o. and 0.5 mg/kg i.v.). Buprenorphine had, as expected, stronger antinociceptive activity (ED50: 1.0 mg/kg p.o. and 0.04 mg/kg i.v.). Fifteen minutes after oral administration of 40 mg/kg flupirtine, the pain threshold in the electrostimulated pain test was increased by 54%. The maximal antinociceptive effect was observed 30 minutes after dosing. The analgesia lasted at least 75 minutes. Codeine significantly elevated the pain threshold 15 minutes after dosing. Its maximal effect was also reached 30 min after application but the antinociceptive activity wore off earlier than after flupirtine. The intracerebroventricular and intrathecal administration of flupirtine also caused dose dependent antinociceptive activity in dose ranges which, when applied systematically, did not produce analgesia in rats. The antinociceptive activity of flupirtine was not abolished by naloxone whether given orally or by the intraventricular or intrathecal routes. In opiate receptor binding studies flupirtine had no affinity for mu, delta or kappa opiate receptors at the highest concentration used (10(-5) M). Whereas buprenorphine and tramadol showed a striking similarity in the pharmaco-electroencephalogram recorded from different parts of the brain (frontal cortex, thalamus, striatum and the mesencephalic reticular formation) of the freely moving rat, flupirtine was clearly different in action. It produced dose dependent increases in nearly all frequency bands but its effects were different from those of the minor tranquillizer diazepam and the anticonvulsant phenobarbitone. These findings show that the central antinociceptive activity of flupirtine is not based on an opiate mechanism and is not comparable with that of diazepam and phenobarbitone.
Asunto(s)
Aminopiridinas/farmacología , Analgésicos/farmacología , Nociceptores/efectos de los fármacos , Aminopiridinas/metabolismo , Analgésicos/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Evaluación Preclínica de Medicamentos/métodos , Electroencefalografía , Femenino , Masculino , Ratones , Dimensión del Dolor/métodos , Ratas , Ratas Endogámicas , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismoRESUMEN
The mechanisms of the antinociceptive action of flupirtine, a novel non-opioid analgesic, were investigated in animals. It was found that this effect could be abolished by pre-treatment with reserpine. Furthermore, it could be dose-dependently antagonized by yohimbine and changes in the EEG of the rat observed after administration of flupirtine were closely related to those obtained after giving clonidine. On these pharmacological results, it is likely that the antinociceptive activity of flupirtine is due to activation of descending noradrenergic pathways.