RESUMO
In an attempt to explain a loss of cross-tolerance between morphine and methadone and an increased tolerance to methadone lethality in morphine-dependent mice administered methadone orally for six days, the possibility that methadone was stimulating its own metabolism was investigated. It was found that methadone did enhance its own metabolism two-fold. This increase in activity correlated with the development of tolerance to the lethal effects of methadone as measured by an elevation of the oral methadone LD50. Furthermore, SKF-525A, a potent microsomal inhibitor, abolished this tolerance. The intracerbroventricular methadone LD50 was not altered by six days administration of oral methadone, suggesting that the tolerance observed was dispositional in nature.
Assuntos
Metadona/farmacologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Tolerância a Medicamentos , Indução Enzimática/efeitos dos fármacos , Humanos , Inativação Metabólica , Dose Letal Mediana , Fígado/enzimologia , Masculino , Camundongos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Proadifeno/farmacologiaAssuntos
Naloxona/análogos & derivados , Naltrexona/farmacologia , Preparações Farmacêuticas/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Depressão Química , Implantes de Medicamento , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Oxigenases de Função Mista/metabolismo , Naltrexona/metabolismo , Preparações Farmacêuticas/sangue , Fatores de TempoAssuntos
Dextropropoxifeno/farmacologia , Oxigenases de Função Mista/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Indução Enzimática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Oxigenases de Função Mista/metabolismo , Fenobarbital/farmacologia , Proadifeno/farmacologia , Proteínas/metabolismoRESUMO
SKF 525-A, given i.p. to mice at doses from 50 to 100 mg/kg, had analgesic activity approximately 40% the analgesic potency of d-propoxyphene HCl, a chemically similar narcotic. While the analgesia produced by propoxyphene was totally antagonized by naloxone, however, that produced by SKF 525-A was only partly reversed. We suspect that SKF 525-A may exert its antinociceptive actions partly by an interaction with CNS narcotic receptors and partly by a nonspecific sedating action.
Assuntos
Analgésicos , Naloxona/farmacologia , Proadifeno/farmacologia , Animais , Dextropropoxifeno/farmacologia , Masculino , Camundongos , Proadifeno/antagonistas & inibidores , Reflexo/efeitos dos fármacosRESUMO
Chronically-administered ethanol, not impaired nutrition, exerts a specific effect to decrease myelination as measured by the activity of the marker enzyme for myelin, 2',3'-cyclic nucleotide 3'-phosphohydrolase.
Assuntos
Alcoolismo/metabolismo , Encéfalo/metabolismo , Etanol/farmacologia , Proteínas da Mielina/biossíntese , Distúrbios Nutricionais/complicações , Alcoolismo/complicações , Animais , Feminino , Humanos , CamundongosAssuntos
Dextropropoxifeno/farmacologia , Microssomos Hepáticos/metabolismo , Oxigenases de Função Mista/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Tolerância a Medicamentos , Humanos , Masculino , Metadona/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Dependência de Morfina/metabolismo , Pentobarbital/farmacologia , Proadifeno/farmacologiaAssuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Camundongos Endogâmicos/fisiologia , Morfina/farmacologia , Norepinefrina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Humanos , Masculino , Camundongos , Dependência de Morfina/metabolismo , Naloxona/farmacologia , Especificidade da EspécieRESUMO
Five different strains of mice were investigated for their suitability to serve as models for the study of long-term effects of propoxyphene napsylate (PN) on narcotic-dependent mice. The NIH/Swiss outbred strain proved to be most suitable because of its high liability to manifest physical dependence on morphine. Following removal of subcutaneously-implanted morphine pellets from the mice, the incidence of spontaneous withdrawal jumping was used as a quantifiable criterion of physical dependence. An orally administered suspension of PN suppressed the withdrawal jumping in a dose-dependent manner. However, chronic (daily) administration of PN at doses high enough to prevent withdrawal jumping was characterized by a high degree of toxicity.