Localization and function of NK(3) subtype tachykinin receptors of layer V pyramidal neurons of the guinea-pig medial prefrontal cortex.

The NK(3) subtype of tachykinin receptor has been implicated as a modulator of synaptic transmission in several brain regions, including the cerebral cortex. The localization and expression of NK(3) receptors within the brain vary from species to species. In addition, the pharmacology of NK(3) receptor-specific antagonists shows significant species variability. Among commonly used animal models, the pharmacology of the guinea-pig NK(3) receptor most closely resembles that of the human NK(3) receptor. Here, we provide anatomical localization studies, receptor binding studies, and studies of the electrophysiological effects of NK(3) receptor ligands of guinea-pig cortex using two commercially available ligands, the NK(3) receptor peptide analog agonist senktide, and the quinolinecarboxamide NK(3) receptor antagonist SB-222,200. Saturation binding studies with membranes isolated from guinea-pig cerebral cortex showed saturable binding consistent with a single high affinity site. Autoradiographic studies revealed dense specific binding in layers II/III and layer V of the cerebral cortex. For electrophysiological studies, brain slices were prepared from prefrontal cortex of 3- to 14-day-old guinea pigs. Whole cell recordings were made from layer V pyramidal neurons. In current clamp mode with a K(+)-containing pipette solution, senktide depolarized the pyramidal neurons and led to repetitive firing of action potentials. In voltage clamp mode with a Cs(+)-containing pipette solution, senktide application produced an inward current and a concentration-dependent enhancement of the amplitude and the frequency of spontaneous excitatory postsynaptic potentials. The glutamatergic nature of these events was demonstrated by block by glutamate receptor antagonists. The effects of senktide were blocked by SB-222,200, an NK(3) receptor antagonist. Taken together, these results are consistent with a functional role for NK(3) receptors located on neurons in the cerebral cortex. In layer V pyramidal neurons of the medial prefrontal cortex, activation of the NK(3) receptor system plays an excitatory role in modulating synaptic transmission.

[The neurogenic mechanisms of ocular inflammation and their modulation under local treatment with indomethacin]. / Mecanisme neurogene ale inflamatiei oculare si modularea lor sub tratament local cu indometacin.

Neurogenic modulation of the inflammation is an essential mechanism of initiate and conditionate an inflammatory reaction. SP, NKA and NKB--neurokinins are involved in the modulation of the local ocular inflammation initiated by the surgical perforating trauma of the anterior pole. They determine the increase of vascular permeability and the breakdown of the aqueous-humor-blood barrier by direct action on the endothelial vascular receptors and by indirect mechanism (releases prostaglandins). This effect is demonstrated by the increase of the blue Evans concentration in the aqueous-humor after local application of SP, NKA and NKB in a dose-dependent manner. Local treatment with non-steroidal-antiinflammatory drugs like Indomethacin stabilizes the aqueous-humor-blood barrier, by diminishing the local effect of neurokinins. By increasing the vascular permeability SP, NKA and NKB make an important linkage by which the nervous system mediators contribute to the modulation of eye inflammatory responses whose intimate mechanisms are not entirely known yet.

Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists.

AIM: To develop nonpeptide tachykinin NK3 antagonists. METHODS: Five tachykinin NK3 antagonists were synthesized. Receptor binding assay and oral absorption study were made. RESULTS: The 4,4-disubstituted piperidine compounds (1b, 1c, and 1d) showed stronger activities (IC50 = 5.9, 6.2, and 11 nmol.L-1, respectively) than the monosubstituted ring compound 1e (IC50 = 17 nmol.L-1). 4-Phenyl (1b) and 4-phenylsulfonylmethyl (1c) compounds were more active than the 4-fluorobenzyl compound (1d). All antagonists were found to be orally absorbable, the T1/2 of 1b (6.4 h) was more than three-fold longer than that of 1a (1.9 h). CONCLUSION: Compound 1b had the best binding activity (IC50 = 5.9 nmol.L-1) and the best AUC (2081 micrograms.h.L-1).

Effects of central neuromedin B and related peptides on blood glucose.

Bombesin (Bn), a peptide of amphibian origin, has been shown to induce hyperglycemia when injected centrally. In recent years, two families of Bn-like peptides have been isolated from the mammalian brain: the gastrin releasing peptide (GRP) type and neuromedin B (NB) type. Distinct receptor subtypes with different mRNAs have also been identified for NB versus GRP/Bn using hybridization and receptor binding studies. It is thus possible that those two families of peptides may display distinct pharmacological profiles. The objective of the current experiment was to determine whether the NB-like peptides could also affect blood glucose levels. The peptide analogs utilized were Bn, NB-10, NAcNB-10 and NB-32 (0, 0.031, 0.062, 0.31, 0.62, 3.1 nmol/3 microliters; i.c.v.). Male rats, chronically implanted with 4th ventricular cannula, were injected with the various neuropeptide doses using the Latin square design. Blood samples were collected (120 microliters) from the tail immediately preceding and at 15, 30 and 60 min following peptide administration. Bn elevated glucose for over 60 min and this effect was maximal at 30 min. NB-10 and NAcNB-10 only slightly elevated plasma glucose. NB-32 elevated plasma glucose at all doses tested, the effect being evident up to 60 min at the highest dose. Our data indicate that at equimolar doses (0.31 nM) NB analogues elevate blood glucose with a lower efficacy than Bn (Bn > NB-32 > NB-10 > or = NAcNB-10). NB-32 appears more potent and efficacious than the other NB congeners used.(ABSTRACT TRUNCATED AT 250 WORDS)