RESUMEN
Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.
Asunto(s)
Ansiedad/tratamiento farmacológico , Temperatura Corporal/efectos de los fármacos , Fluoxetina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Fiebre , Fluoxetina/administración & dosificación , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Especificidad de la Especie , Estrés Psicológico , TelemetríaRESUMEN
This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.
Asunto(s)
Amidas/farmacocinética , Antagonistas del Receptor de Bradiquinina B1 , Naftalenos/farmacocinética , Dimensión del Dolor/métodos , Pirrolidinas/farmacocinética , Médula Espinal/efectos de los fármacos , Amidas/administración & dosificación , Animales , Carragenina/administración & dosificación , Carragenina/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrofisiología/métodos , Pie , Miembro Posterior , Calor/efectos adversos , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Hiperalgesia/prevención & control , Hipersensibilidad/etiología , Hipersensibilidad/fisiopatología , Inyecciones Intravenosas , Inyecciones Espinales , Masculino , Morfina/farmacología , Naftalenos/administración & dosificación , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Desempeño Psicomotor/efectos de los fármacos , Pirrolidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Médula Espinal/fisiologíaRESUMEN
Substance P receptor [neurokinin 1 (NK1] antagonists (SPAs) represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK1 receptor antagonist 1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-phenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine (L-760735) caused an increase in DRN neuronal firing rate. However, unlike chronic treatment with fluoxetine, there was no detectable 5-HT1A autoreceptor desensitization. In vitro electrophysiological investigation showed that these effects were not mediated by a direct action in the DRN, an observation supported by immunocytochemical analysis that identified the lateral habenula (LHb) as a more likely site of action. Subsequently, we found that local application of L-760735 into the LHb increased firing in the DRN, which, together with our data showing that L-760735 increased metabolic activity in the cingulate cortex, amygdala, LHb, and DRN, indicates that the effects of L-760735 may be mediated by disinhibition of forebrain structures acting via a habenulo raphe projection. These findings support other evidence for an antidepressant profile of SPAs and suggest that regulation of DRN neuronal activity may contribute to their antidepressant mechanism of action but in a manner that is distinct from monoamine reuptake inhibitors.