RESUMEN
Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (Ñ<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.
Asunto(s)
Dependencia de Morfina , Síndrome de Abstinencia a Sustancias , Tuftsina , Ratas , Animales , Morfina , Dependencia de Morfina/tratamiento farmacológico , Naloxona/farmacología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , DiazepamRESUMEN
Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.
Asunto(s)
Dipéptidos/farmacología , Dependencia de Morfina/tratamiento farmacológico , Morfina/antagonistas & inhibidores , Antagonistas de Narcóticos/farmacología , Peptidomiméticos/farmacología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Animales no Consanguíneos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Expresión Génica , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inyecciones Intraperitoneales , Masculino , Morfina/efectos adversos , Dependencia de Morfina/genética , Dependencia de Morfina/metabolismo , Dependencia de Morfina/fisiopatología , Narcóticos/efectos adversos , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatologíaRESUMEN
Activities of noncompetitive NMDA receptor antagonists (aminoadamantane derivatives) were assessed in random-bred rats with modeled morphine withdrawal syndrome. A single intraperitoneal injection of hemantane (10 or 20 mg/kg) significantly and dose-dependently moderated some behavioral symptoms (teeth-chattering, ptosis, and vocalization) and reduced total score of morphine withdrawal syndrome. In morphine-abstinent rats, hemantane partially prevented the decrease in the thresholds of tactile sensitivity, but had no effect on locomotor activity and body weight loss. Under conditions of morphine withdrawal, intraperitoneal injection of amantadine (10 or 20 mg/kg) decreased motor activity and promoted body weight loss in parallel with the development of mechanical allodynia, but had no effect on the total withdrawal score. Comparison of aminoadamantane derivatives by behavioral and physiological parameters demonstrated the advantage of hemantane during morphine abstinence indicating the need of its study as a promising anti-addiction remedy.
Asunto(s)
Adamantano/análogos & derivados , Amantadina/farmacología , Dependencia de Morfina/fisiopatología , Antagonistas de Narcóticos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Adamantano/farmacología , Animales , Expresión Génica , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Inyecciones Intraperitoneales , Masculino , Morfina/administración & dosificación , Dependencia de Morfina/genética , Dependencia de Morfina/metabolismo , Actividad Motora/efectos de los fármacos , Ratas , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Pérdida de Peso/efectos de los fármacosRESUMEN
Previously, we synthesized a dimeric dipeptide mimetic of the brain-derived neurotrophic factor (BDNF) loop 4, GSB-106, which, similarly to BDNF, activated TrkB, PI3K/AKT, and MAPK/ERK. When administered systemically, it exhibited neuroprotective, antidepressant, and antidiabetic activities and stimulated neurogenesis and synaptogenesis. In this study, we established that GSB-106 also exhibits the analgesic activity, typical for BDNF, which was revealed in rats in hot plate and tail flick tests 0.5-48 h after intraperitoneal injection at doses of 0.1 and 1 mg/kg.
Asunto(s)
Analgésicos , Factor Neurotrófico Derivado del Encéfalo , Dipéptidos , Peptidomiméticos , Analgésicos/química , Analgésicos/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/química , Factor Neurotrófico Derivado del Encéfalo/farmacología , Dipéptidos/química , Dipéptidos/farmacología , Humanos , Masculino , Peptidomiméticos/química , Peptidomiméticos/farmacología , Estructura Secundaria de Proteína , RatasRESUMEN
The anxiolytic effects of GB-115, a retroanalogue of cholecystokinin-4, administered orally to outbred and inbred animals with different level of emotionality, were studied in the open field test and elevated plus-maze test. The anxiolytic effect of talanax was observed in outbred mice (0.1-0.5 mg/kg) and in inbred BALB/c mice (0.1 and 5.0 mg/kg) in the open field test. GB-115 increased the time of entries into open arms in outbred rats (0.5-0.7 mg/kg) and in BALB/c mice (0.1 mg/kg). These data confirmed the dependence of GB-115 effect on the phenotype of emotional stress response and demonstrated a shift of anxiolytic doses of the preparation from 0.006-0.100 mg/kg in intraperitoneal administration to 0.1-5.0 mg/kg in oral treatment.
Asunto(s)
Ansiolíticos/farmacología , Colecistoquinina/farmacología , Dipéptidos/farmacología , Estrés Psicológico/tratamiento farmacológico , Tetragastrina/farmacología , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Colecistoquinina/análogos & derivados , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , RatasAsunto(s)
Dipéptidos/farmacología , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Receptor trkA/metabolismo , Animales , Animales no Consanguíneos , Línea Celular , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Morfolinas/farmacología , Factor de Crecimiento Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Umbral del Dolor/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Behavioral and physiological indices which could be symptoms of individual Wistar rats' sensitivity to the development of physical dependence on morphine, were studied. This state was induced in three different ways: (1) by i.p. injection of increasing doses of the drug; (2) by i.p. injection of morphine as a reward of a rat's visit to a certain compartment of the Y-maze; (3) by voluntary drinking a morphine solution. Animals with high sensitivity to the development of dependence induced by the first way initially demonstrated intensive ambulation and low rearing in the open field and low nociception in the tail flick test. In the second case the 'predisposed' animals had initially higher ambulation also in comparison with the 'resistant' ones, but did not demonstrate significant withdrawal symptoms. The rats imbibing morphine solution exhibited a withdrawal syndrome, low level of initial nociception and received more electrocutaneous stimuli in the Vogel test. Thus, marked differences of sensitivity to the development of morphine dependence are correlated with some initial behavioural and physiological indices and may be genetically and neurochemically determined.