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NK1 Receptors (nk1 + receptor)
Terms modified by NK1 Receptors Selected AbstractsThe murine neurokinin NK1 receptor gene contributes to the adult hypoxic facilitation of ventilationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Krzysztof Ptak Abstract Substance P and neurokinin-1 receptors (NK1) modulate the respiratory activity and are expressed early during development. We tested the hypothesis that NK1 receptors are involved in prenatal development of the respiratory network by comparing the resting respiratory activity and the respiratory response to hypoxia of control mice and mutant mice lacking the NK1 receptor (NK1,/,). In vitro and in vivo experiments were conducted on neonatal, young and adult mice from wild-type and NK1,/, strains. In the wild strain, immunohistological, pharmacological and electrophysiological studies showed that NK1 receptors were expressed within medullary respiratory areas prior to birth and that their activation at birth modulated central respiratory activity and the membrane properties of phrenic motoneurons. Both the membrane properties of phrenic motoneurons and the respiratory activity generated in vitro by brainstem-spinal cord preparation from NK1,/, neonate mice were similar to that from the wild strain. In addition, in vivo ventilation recordings by plethysmography did not reveal interstrain differences in resting breathing parameters. The facilitation of ventilation by short-lasting hypoxia was similar in wild and NK1,/, neonates but was significantly weaker in adult NK1,/, mice. Results demonstrate that NK1 receptors do appear to be necessary for a normal respiratory response to short-lasting hypoxia in the adult. However, NK1 receptors are not obligatory for the prenatal development of the respiratory network, for the production of the rhythm, or for the regulation of breathing by short-lasting hypoxia in neonates. [source] A flexible approach to the design of new potent substance P receptor ligandsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001R. Millet The development of small-molecule antagonists of the substance-P-preferring tachykinin NK1 receptor offers an excellent opportunity to exploit these molecules as novel therapeutic agents in diverse pathologies such as depression, emesis or asthma. GR71251 has previously been identified as a potent and selective substance-P-receptor antagonist. We have therefore undertaken the synthesis of new pseudopeptidic analogues based on the C-terminal sequence of GR71251. The evaluation of binding affinities toward NK1 and NK2 receptors has enabled us to propose new selective NK1 ligands with high affinity. Structure-activity relationships showed that the Trp-OBzl(CF3)2 moiety is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a useful starting point for new substance P antagonists and represent an attractive lead series for further studies on the design of specific NK1 antagonists. [source] Comparison of Localization of the Neurokinin 1 Receptor and Nitric Oxide Synthase with Calbindin D Labelling in the Rat Spinal CordANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 3 2000M. Nazli Summary A comparison of the localization of the neurokinin 1 (NK1) receptor and nitric oxide synthase with calbindin D labelling in the lumbar spinal cord was carried out in the rat using immunocytochemistry. Considerable regional variations were observed. Application of the antibody to calbindin D resulted in dense staining in laminae I and II and light staining in the other laminae. Occasional scattered cells were seen in the deep laminae and in the lamina X, the ventral horn and the lateral spinal nucleus. The results indicate that neurones expressing calbindin D, NK1 receptor and NOS are three separate populations in the dorsal horn of the lumbar spinal cord. [source] Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransductionARTHRITIS & RHEUMATISM, Issue 1 2003S. J. Millward-Sadler Objective To assess whether substance P and the corresponding neurokinin 1 (NK1) receptor are expressed in human articular cartilage, and whether these molecules have a role in chondrocyte mechanotransduction. Methods Transgenic studies, immunohistochemistry, Western blotting, and reverse transcriptase,polymerase chain reaction were used to assess the expression of the preprotachykinin (PPT) gene, substance P, and NK1 in developing mice, in adult human articular cartilage, and in human chondrocytes in culture. Chondrocytes obtained from PPT knockout mice and human articular chondrocytes were mechanically stimulated in the presence or absence of inhibitors of substance P signaling, and cell membrane potentials or relative levels of aggrecan messenger RNA (mRNA) were measured. Results Replacing a region of the PPT gene transcriptional site that contains a dominant repressor of the proximal promoter activity with the constitutive minimal promoter of the human ,-globin promoter allowed expression of a marker gene in areas of chondrogenesis during mouse development and in adult chondrocytes grown in culture. Adult human articular chondrocytes expressed endogenous PPT mRNA, substance P, and the corresponding NK1 receptor in vivo and in vitro. Blockade of substance P signaling by a chemical antagonist to the NK1 receptor inhibited chondrocyte responses to mechanical stimulation. Conclusion Substance P is expressed in human articular cartilage and is involved in chondrocyte mechanotransduction via the NK1 receptor in an autocrine and paracrine manner. This suggests that substance P and the NK1 receptor have roles in the maintenance of articular cartilage structure and function that were previously unrecognized. [source] The murine neurokinin NK1 receptor gene contributes to the adult hypoxic facilitation of ventilationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Krzysztof Ptak Abstract Substance P and neurokinin-1 receptors (NK1) modulate the respiratory activity and are expressed early during development. We tested the hypothesis that NK1 receptors are involved in prenatal development of the respiratory network by comparing the resting respiratory activity and the respiratory response to hypoxia of control mice and mutant mice lacking the NK1 receptor (NK1,/,). In vitro and in vivo experiments were conducted on neonatal, young and adult mice from wild-type and NK1,/, strains. In the wild strain, immunohistological, pharmacological and electrophysiological studies showed that NK1 receptors were expressed within medullary respiratory areas prior to birth and that their activation at birth modulated central respiratory activity and the membrane properties of phrenic motoneurons. Both the membrane properties of phrenic motoneurons and the respiratory activity generated in vitro by brainstem-spinal cord preparation from NK1,/, neonate mice were similar to that from the wild strain. In addition, in vivo ventilation recordings by plethysmography did not reveal interstrain differences in resting breathing parameters. The facilitation of ventilation by short-lasting hypoxia was similar in wild and NK1,/, neonates but was significantly weaker in adult NK1,/, mice. Results demonstrate that NK1 receptors do appear to be necessary for a normal respiratory response to short-lasting hypoxia in the adult. However, NK1 receptors are not obligatory for the prenatal development of the respiratory network, for the production of the rhythm, or for the regulation of breathing by short-lasting hypoxia in neonates. [source] A flexible approach to the design of new potent substance P receptor ligandsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001R. Millet The development of small-molecule antagonists of the substance-P-preferring tachykinin NK1 receptor offers an excellent opportunity to exploit these molecules as novel therapeutic agents in diverse pathologies such as depression, emesis or asthma. GR71251 has previously been identified as a potent and selective substance-P-receptor antagonist. We have therefore undertaken the synthesis of new pseudopeptidic analogues based on the C-terminal sequence of GR71251. The evaluation of binding affinities toward NK1 and NK2 receptors has enabled us to propose new selective NK1 ligands with high affinity. Structure-activity relationships showed that the Trp-OBzl(CF3)2 moiety is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a useful starting point for new substance P antagonists and represent an attractive lead series for further studies on the design of specific NK1 antagonists. [source] Evidence for functional NK1 -tachykinin receptors on motor neurones supplying the circular muscle of guinea-pig small and large intestineNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2000Bian The guinea-pig intestine was investigated to determine which neurones are excited via NK1 receptors. The specific NK1 receptor agonists [Sar9, Met(O2)11]-SP and septide contracted the circular muscle of all regions via a tetrodotoxin (TTX)-insensitive mechanism. In the proximal colon, they also evoked a TTX-sensitive relaxation; in the distal colon, the contractions were larger when nerve impulses were blocked with TTX, indicating that the agonists excited inhibitory motor neurones. In the duodenum and ileum, TTX reduced agonist-evoked contractions indicating that excitatory motor neurones were activated. In the presence of indomethacin, TTX enhanced contractions of ileal circular muscle evoked by these agonists suggesting that NK1 receptors were on inhibitory motor neurones. Blockade of nitric oxide synthase (NOS) enhanced NK1 receptor agonist evoked contractions of duodenal circular muscle, indicating that the agonists excite inhibitory motor neurones in duodenum. Neurones immunoreactive for NK1 receptors were studied in the duodenum and distal colon. As reported previously for the ileum,1 some neurones were immunoreactive for NOS and had Dogiel type I morphology; features characteristic of inhibitory motor neurones. In conclusion, there are functional NK1 receptors on excitatory and inhibitory motor neurones in the guinea-pig small intestine and on inhibitory motor neurones in the colon. [source] Substance P presynaptically depresses the transmission of sensory input to bronchopulmonary neurons in the guinea pig nucleus tractus solitariiTHE JOURNAL OF PHYSIOLOGY, Issue 2 2003Shin-ichi Sekizawa Substance P modulates the reflex regulation of respiratory function by its actions both peripherally and in the CNS, particularly in the nucleus tractus solitarii (NTS), the first central site for synaptic contact of the lung and airway afferent fibres. There is considerable evidence that the actions of substance P in the NTS augment respiratory reflex output, but the precise effects on synaptic transmission have not yet been determined. Therefore, we determined the effects of substance P on synaptic transmission at the first central synapses by using whole-cell voltage clamping in an NTS slice preparation. Studies were performed on second-order neurons in the slice anatomically identified as receiving monosynaptic input from sensory nerves in the lungs and airways. This was done by the fluorescent labelling of terminal boutons after 1,1,-dioctadecyl-3,3,3,,3,-tetra-methylindocarbo-cyanine perchlorate (DiI) was applied via tracheal instillation. Substance P (1.0, 0.3 and 0.1 ,M) significantly decreased the amplitude of excitatory postsynaptic currents (eEPSCs) evoked by stimulation of the tractus solitarius, in a concentration-dependent manner. The decrease was accompanied by an increase in the paired-pulse ratio of two consecutive eEPSCs, and a decrease in the frequency, but not the amplitude, of spontaneous EPSCs and miniature EPSCs, findings consistent with a presynaptic site of action. The effects were consistently and significantly attenuated by a neurokinin-1 (NK1) receptor antagonist (SR140333, 3 ,M). The data suggest a new site of action for substance P in the NTS (NK1 receptors on the central terminals of sensory fibres) and a new mechanism (depression of synaptic transmission) for regulating respiratory reflex function. [source] Role of the Neurokinin-1 Receptors in Ejaculation in Anesthetized RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 1 2009Pierre Clement PhD ABSTRACT Introduction., Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. Aim., The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. Methods., Ejaculation was induced in anesthetized rats by intracerebroventricular (icv) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (ip), icv, or intrathecal (it) (third lumbar spinal segment; L3) administration. Main Outcome Measures., Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. Results., Upon ip, icv, or it administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following icv or it administration. Conclusion., These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors. Clement P, Peeters M, Bernabe J, Laurin M, Alexandre L, and Giuliano F. Role of the neurokinin-1 receptors in ejaculation in anesthetized rats. J Sex Med 2009;6:126,134. [source] Role of NK1 and NK2 receptors in mouse gastric mechanical activityBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2006Flavia Mulè The aim of the present study was to examine the role of NK1 and NK2 receptors in the control of mechanical activity of mouse stomach. In this view, the motor effects induced by NK1 and NK2 receptor agonists and antagonists were analyzed, measuring motility as intraluminal pressure changes in mouse-isolated stomach preparations. In parallel, immunohistochemical studies were performed to identify the location of NK1 and NK2 receptors on myenteric neurons and smooth muscle cells. Substance P (SP) induced biphasic effects: a contraction followed by relaxation; neurokinin A (NKA) and [, -Ala8]-NKA(4,10), selective agonist of NK2 receptors, evoked concentration-dependent contractions, whereas [Sar9, Met(O2)11]-SP, selective agonist of NK1 receptors, induced concentration-dependent relaxation. SR48968, NK2 receptor antagonist, did not modify the spontaneous activity and reduced the contractile effects induced by tachykinins without affecting the relaxation. SR140333, NK1 receptor antagonist, did not modify the spontaneous activity and antagonized the relaxant response to tachykinins, failing to affect the contractile effects. The relaxation to SP or to [Sar9, Met(O2)11]-SP was abolished by tetrodotoxin (TTX) and significantly reduced by N -nitro- L -arginine methyl ester (L -NAME). NK2 -immunoreactivity (NK2 -IR) was seen at the level of the smooth muscle cells of both circular and longitudinal muscle layers. NK1 -immunoreactive (NK1 -IR) neurons were seen in the myenteric ganglia and NK1/nNOS double labeling revealed that some neurons were both NK1 -IR and nNOS-IR. These results suggest that, in mouse stomach, NK1 receptors, causing relaxant responses, are present on nitrergic inhibitory myenteric neurons, whereas NK2 receptors, mediating contractile responses, are present at muscular level. British Journal of Pharmacology (2006) 147, 430,436. doi:10.1038/sj.bjp.0706645 [source] | |||||||||||||