sr-142801 and septide

Tachykinins are important mediators in neuromuscular signalling but have not been thoroughly characterised in the mouse gut. We investigated the participation of tachykinin receptors in contractility of circular muscle strips of the mouse ileum.. Electrical field stimulation (EFS) of excitatory nonadrenergic noncholinergic (NANC) nerves induced frequency-dependent contractions which were mimicked by substance P (SP). Desensitisation of SP and NK(1), NK(2) or NK(3) receptors significantly reduced contractions to EFS. The NK(1) receptor blocker RP67580 significantly inhibited NANC contractions to EFS. The NK(2) and NK(3) receptor blockers nepadutant and SR142801 did not affect NANC contractions per se but increased the RP67580-induced inhibition of NANC contractions to EFS. Contractions to SP were significantly reduced by RP67580 but not affected by nepadutant or SR142801. The NK(1) and NK(2) receptor agonists, septide and [beta-ala(8)]-NKA 4-10 (beta-A-NKA), respectively, but not the NK(3) receptor agonist senktide-induced dose-dependent contractions. Atropine inhibited and l-NNA augmented contractions to septide. Contractions to beta-A-NKA were insensitive to atropine but augmented by l-NNA.. Tachykinins mediate NANC contractions to EFS in the mouse small intestine. Endogenously released tachykinins activate mainly NK(1) receptors, located on cholinergic nerves and smooth muscle cells and, to a lesser degree, NK(2) and NK(3) receptors, most likely located presynaptically.

Topics: Action Potentials; Analgesics; Animals; Antipsychotic Agents; Atropine; Electric Stimulation; Ileum; Indoles; Isoindoles; Mice; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Neurons; Nitroarginine; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P

The present experiments investigated the role of neurokinin-1 (NK(1)) and neurokinin-3 (NK(3)) receptors on the activity of the locus coeruleus (LC)-noradrenergic system by using a dual probe microdialysis technique in anesthetized guinea pigs. The local application in the LC of the selective NK(1) receptor agonists [SAR(9),Met(O(2))(11)]-SP (10 microM) and septide (1 microM) as well as the selective NK(3) receptor agonist senktide (1 microM), enhanced the extracellular norepinephrine (NE) levels in the prefrontal cortex. The enhancing effect of [SAR(9),Met(O(2))(11)]-SP was completely blocked by the peripheral administration of the selective non peptide NK(1) and NK(3) receptor antagonists, GR 205171 (1 mg/kg, i.p.) and SR 142801 (0.1 mg/kg, i.p.), respectively, whereas SR 142806 (0.1 mg/kg, i.p.) the inactive enantiomer of SR 142801 had no effect. Moreover, the [SAR(9),Met(O(2))(11)]-SP-induced increase in LC DOPAC concentrations, is only antagonized by GR 205171. In contrast, only SR 142801 (0.3 mg/kg, i.p.) could block stereoselectively the senktide-evoked increase in NE levels. Both [SAR(9),Met(O(2))(11)]-SP and senktide effects were blocked by local infusion into the LC of SR 142801 (10(-9) M). These results demonstrate that stimulation of NK(1) and NK(3) receptors located in the LC area modulates the activity of the LC-NE system, and that the excitatory effects of NK(1) receptor agonists require NKB/NK(3) receptor activation in the LC.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antiemetics; Dose-Response Relationship, Drug; Guinea Pigs; Locus Coeruleus; Male; Neural Pathways; Neurokinin-1 Receptor Antagonists; Neurons; Norepinephrine; Peptide Fragments; Piperidines; Prefrontal Cortex; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-1; Receptors, Neurokinin-3; Substance P; Tetrazoles

Using a microsuperfusion method in vitro, the effects of the NK1, NK2, and NK3 tachykinin receptor antagonists SR140333, SR48968, and SR142801, respectively, on the NMDA-evoked release of [3H]-acetylcholine were investigated after both acute and chronic suppression of dopamine transmission in striosomes and matrix of the rat striatum. NMDA (1 mm) alone or with D-serine (10 microm) in the presence of alpha-methyl-p-tyrosine (100 microm) markedly enhanced the release of [3H]-acetylcholine through a dopamine-independent inhibitory process. In both conditions, as well as after chronic 6-OHDA-induced denervation of striatal dopaminergic fibers, SR140333, SR48968, or SR142801 (0.1 microm each) reduced the NMDA-evoked release of [3H]-acetylcholine in the matrix but not in striosome-enriched areas. These responses were selectively abolished by coapplication with NMDA of the respective tachykinin agonists, septide, [Lys5,MeLeu9,Nle10]NKA(4-10), or senktide. Distinct mechanisms are involved in the effects of the tachykinin antagonists because the inhibitory response of SR140333 was additive with that of either SR48968 or SR142801. In addition, the SR140333-evoked response remained unchanged, whereas those of SR48968 and SR142801 were abolished in the presence of N(G)-monomethyl-l-arginine (nitric oxide synthase inhibitor). Therefore, in the matrix but not in striosomes, the acute or chronic suppression of dopamine transmission unmasked the facilitatory effects of endogenously released substance P, neurokinin A, and neurokinin B on the NMDA-evoked release of [3H]-acetylcholine. Whereas substance P and neurokinin A are colocalized in same efferent neurons, their responses involve distinct circuits because the substance P response seems to be mediated by NK1 receptors located on cholinergic interneurons, while those of neurokinin A and neurokinin B are nitric oxide-dependent.

Topics: Acetylcholine; Animals; Benzamides; Corpus Striatum; Dopamine; Dopamine Antagonists; Enzyme Inhibitors; In Vitro Techniques; Male; N-Methylaspartate; Neural Inhibition; Neurons; Oxidopamine; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Tachykinin; Substance P; Synaptic Transmission; Tachykinins; Time Factors

1. The role of NK1 and NK3 receptors in synaptic transmission between myenteric neurons during motility reflexes in the guinea-pig ileum was investigated by recording intracellularly the reflex responses of the circular muscle to distension or compression of the mucosal villi. Experiments were performed in a three-chambered organ bath that enabled drugs to be selectively applied to different sites along the reflex pathways. 2. When applied in the recording chamber, an NK1 receptor antagonist, SR140333 (100 nM), reduced by 40-50% the amplitudes of inhibitory junction potentials (i.j.ps) evoked in the circular muscle by activation of descending reflex pathways. This effect was abolished when synaptic transmission in the stimulus region was blocked with physiological saline containing 0.1 mM Ca2+ plus 10 mM Mg2+, leaving only the component of the descending reflex pathway conducted via long anally directed collaterals of intrinsic sensory neurons. 3. SR140333 (100 nM) had no effect on descending reflex i.j.ps when applied to the stimulus region. Ascending reflexes were also unaffected by SR140333 in the stimulus region or between the stimulus and recording sites. 4. Septide (10 nM), an NK1 receptor agonist, enhanced descending reflexes by 30-60% when in the recording chamber. [Sar9,Met(O2)11]substance P had no effect at 10 nM, but potentiated distension-evoked reflexes at 100 nM. 5. A selective NK3 receptor antagonist, SR142801 (100 nM), when applied to the stimulus region, reduced the amplitude of descending reflex responses to compression by 40%, but had no effect on responses to distension. SR142801 (100 nM) had no effect when applied to other regions of the descending reflex pathways. 6. SR142801 (100 nM) only inhibited ascending reflexes when applied at the recording site. However, after nicotinic transmission in the stimulus region was blocked, SR142801 (100 nM) at this site reduced responses to compression. 7. Contractions of the circular muscle of isolated rings of ileum evoked by low concentrations of septide, but not [Sar9,Met(O2)11]substance P, were potentiated by tetrodotoxin (300 nM). 8. Contractile responses evoked by an NK3 receptor agonist, senktide, were non-competitively inhibited by SR142801. After excitatory neuromuscular transmission was blocked, senktide produced inhibitory responses that were also antagonised by SR142801, but to a lesser extent and in an apparently competitive manner. 9. These results indicate that tachykinins acting v

Topics: Animals; Female; Gastrointestinal Motility; Guinea Pigs; Ileum; In Vitro Techniques; Male; Neurokinin-1 Receptor Antagonists; Neurons; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Quinuclidines; Receptors, Neurokinin-1; Receptors, Neurokinin-3; Substance P; Synaptic Transmission