Influence of tachykinin NK2 receptors on intestinal sensitivity and motility in newborn rats.

The effect of tachykinin neurokinin NK(2) receptors activation on intestinal propulsion and colorectal sensitivity was studied in 7-15 days old newborn rats. In a first set of experiments investigating the intestinal transit, the selective NK(2) receptor agonist, [betaAla(8)]NKA-(4-10) was used. It produced an increase of the small intestinal transit measured by charcoal test of 54%, that was inhibited in a dose-dependent manner by nepadutant ([N(4)-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-L-asparaginyl-L-aspartyl-L-tryptophyl-L-phenylalanyl-L-2,3-diaminopropionyl-L-leucyl]-C-4.2-N-3.5-lactam-C-1.6-N-2.1-lactam), a known selective NK(2) receptor antagonist, orally administered 2-48 h before the challenge with the NK(2) receptor agonist. Nepadutant did not affect the basal intestinal propulsion and showed a good oral bioavailability and long duration of action. In another set of experiments investigating visceral sensitivity, a fixed distension volume of a balloon inserted intrarectally in 14-15 days old newborns rats produced abdominal contractions (AC) that were increased after colonic application of acetic acid (50 microl, 0.5%). In this latter condition nepadutant, at 0.5 and 2.5 mg/kg p.o., significantly reduced the resulting AC. In control rats, untreated with acetic acid, nepadutant did not affect AC evoked by colorectal distension. These findings show for the first time two models to assess intestinal motility and visceral sensitivity in newborn rats and indicate nepadutant as a valuable tool to assess the role of NK(2) receptors in the intestinal propulsive and nociceptive activity in infants.

Chronic L-DOPA treatment increases extracellular glutamate levels and GLT1 expression in the basal ganglia in a rat model of Parkinson's disease.

There is growing experimental evidence for the implication of glutamate-mediated mechanisms both in the pathophysiology of Parkinson's disease and in the development of dyskinesias with long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA). However, the impact of this treatment on glutamate transmission in the basal ganglia has been poorly investigated. In this study, we examined the effects of 6-hydroxydopamine-induced lesion of nigral dopamine neurons with or without subsequent chronic L-DOPA treatment on several parameters of glutamate system function in the rat striatum and substantia nigra pars reticulata. All the lesioned animals treated with L-DOPA developed severe dyskinesias. Extracellular glutamate levels, measured by microdialysis in freely moving conditions, and gene expression of the glial glutamate transporter GLT1, assessed by in situ hybridization, were unaffected by dopamine lesion or L-DOPA treatment alone, but were both markedly increased on the lesion side of rats with subsequent L-DOPA treatment. No change in the expression of the vesicular glutamate transporters vGluT1 and vGluT2 was measured in striatum. These data show that chronic L-DOPA treatment leading to dyskinesias increases basal levels of glutamate function in basal ganglia. The L-DOPA-induced overexpression of GLT1 may represent a compensatory mechanism involving astrocytes to limit glutamate overactivity and subsequent toxic processes.