In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

Emonds‐Alt, Xavier; Doutremepuich, Jean-Daniel; Héaulme, Michel; Néliat, Gervais; Santucci, Vincent; Steinberg, R.; Vilain, P.; Bichon, Daniel; Ducoux, Jean-Philippe; Proietto, Vincenzo; Broeck, Didier Van; Soubrié, Philippe; Fur, G. Le; Brelière, Jean-Claude

doi:10.1016/0014-2999(93)90027-f

Cited by 352 publications

(207 citation statements)

References 32 publications

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“…The hypothesis that NK 1 receptors play a role in neutrophil accumulation induced by carrageenin is supported by additional experiments conducted in wild-type mice pretreated with the selective, long-lasting NK 1 receptor antagonist, SR140333 (4,14). SR140333 (480 nmol/kg i.v.…”

Section: Neutrophil Accumulation In Wild-type and Nk 1 Receptor Knockmentioning

confidence: 96%

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Cao¹,

Pintér²,

Al-Rashed³

et al. 2000

The Journal of Immunology

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We have used tachykinin neurokinin-1 receptor (NK1 receptor) knockout mice to learn of the link between NK1 receptors and neutrophil accumulation in normal naive skin, as compared with inflamed skin. Intradermal substance P (300 pmol) induced edema formation in wild-type mice, but not in NK1 knockout mice, as expected. However, in contrast to IL-1β (0.3 pmol), substance P did not induce neutrophil accumulation in wild-type mice. IL-1β-induced neutrophil accumulation was similar in wild-type and knockout mice, but a significant (p < 0.05) contributory effect of added NK1 agonists, which by themselves have no effect on neutrophil accumulation in normal skin, was observed. The results support the concept that NK1 agonists such as substance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circumstances, the NK1 receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process. We investigated responses to two inflammatory stimuli (carrageenin and zymosan). Neutrophil accumulation was significantly attenuated (p < 0.001) in carrageenin- but not zymosan-induced inflammation in NK1 knockout mice. The carrageenin (500 μg)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at −5 min), in the wild-type group. The bradykinin B1 and B2 receptor antagonists (desArg9[Leu8]bradykinin and HOE 140) each reduced neutrophil accumulation to carrageenin in wild-type animals (p < 0.05), but did not cause further reduction of the suppressed response of knockout mice. The results provide evidence that kinin receptors participate in NK1 receptor-dependent neutrophil accumulation in inflamed mouse skin.

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Section: Neutrophil Accumulation In Wild-type and Nk 1 Receptor Knockmentioning

confidence: 96%

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Cao¹,

Pintér²,

Al-Rashed³

et al. 2000

The Journal of Immunology

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“…Since major potency di erences can arise from di erential rates of metabolism of the various agonists (Sekizawa et al, 1987;Stephens-Smith et al, 1988;Shore & Drazen, 1989), experiments were performed in the presence of an appropriate cocktail of peptidase inhibitors. The e ects of the nonpeptide NK 1 (SR 140,333;Emonds-Alt et al, 1993), NK 2 (SR 48,968;Emonds-Alt et al, 1992 and GR 159,897;Beresford et al, 1995) and NK 3 (SR 142,801;Emonds-Alt et al, 1995;and SB 222,200;Giardina et al, 1996 ± compound 7b) receptor selective antagonists were also examined.…”

Section: Introductionmentioning

confidence: 99%

Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK₂ receptors

Kerr

Thai

Coupar

2000

British J Pharmacology

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“…The inhibitory action of SP on progesterone conversion into 5␣-DHP and 3␣,5␣-THP was mimicked by [Sar-9,Met(O 2 ) 11 ]-SP, a highly selective rNK1 agonist (23,24). In addition, SR140333, a specific antagonist for rNK1 (25)(26)(27), completely blocked the inhibitory effect of SP on 5␣-DHP and 3␣,5␣-THP formation. These results indicate that the action of SP on progesterone conversion into neuroactive derivatives in the spinal sensory circuit is mediated by rNK1, which plays a pivotal role in the generation of inflammatory and neuropathic pain (4)(5)(6)(7)(8)(9).…”

Section: Discussionmentioning

confidence: 96%

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

Patte‐Mensah

Kibaly

Mensah‐Nyagan

2005

Proc. Natl. Acad. Sci. U.S.A.

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A crucial biochemical reaction in vertebrates is progesterone conversion into neuroactive metabolites such as dihydroprogesterone (5␣-DHP) and tetrahydroprogesterone (3␣,5␣-THP), which regulate several neurobiological processes, including stress, depression, neuroprotection, and analgesia. 3␣,5␣-THP is a potent stimulator of type A receptors of GABA, the main inhibitory neurotransmitter. Here, we show that in the spinal sensory circuit progesterone conversion into 5␣-DHP and 3␣,5␣-THP is inhibited dose-dependently by substance P (SP), a major mediator of painful signals. We developed a triple-labeling approach coupled with multichannel confocal microscope analysis, which revealed that, in the spinal cord (SC), SP-releasing afferents project on sensory neurons expressing simultaneously neurokinin 1 receptors (rNK1) and key enzymes catalyzing progesterone metabolism. Evidence for a potent inhibitory effect of SP on 5␣-DHP and 3␣,5␣-THP formation in the SC was provided by combining pulse-chase experiments using neurosteroid ͉ pain ͉ spinal cord ͉ steroids ͉ nervous system T he spinal cord (SC) is a pivotal structure controlling many neurophysiological activities, including somatosensory transmission, locomotion, reflexes, and neurovegetative functions. Primary sensory inputs arising from receptors in various areas of the body are integrated in multisynaptic relays in the SC that convey these inputs toward the brain (1, 2). A variety of molecules, including glutamate, substance P (SP), neurotrophins, calcitonin-gene related peptide, and adenosine triphosphate, are thought to be involved in the central transmission of sensory messages (2, 3). Among these neuromodulators, SP, the role of which is clearly established and well documented, is considered as a key neuropeptide mediating nociceptive message transmission from peripheral afferents to sensory neurons located in the SC dorsal horn (DH) (4-6). In particular, it has been shown that projection neurons in lamina I of rat DH expressing neurokinin 1 receptors (rNK1s) are selectively innervated by SP-containing afferents and respond to noxious stimulation (7). Direct structural-functional evidence for SP-mediated nociceptive transmission has also been provided in cats by multidisciplinary studies that combined various approaches, including intracellular recording from DH neurons in vivo, characterization of these neurons on the basis of their responses to peripheral noxious stimulation, cellular labeling by horseradish peroxidase, and electron microscopic identification of synaptic contacts (6-9). Moreover, intrathecal injection of SP conjugated to the cytotoxin saporin selectively destroyed DH neurons bearing rNK1 and strongly reduced hyperalgesia after capsaicin treatment, indicating that spinal rNK1 neurons are important for the development of hyperalgesia (4, 5). However, intracellular changes or neurochemical modifications that spinal rNK1 neurons undergo during nociception are poorly characterized. This situation hampers the understanding of spinal mechanisms in...

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In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

Cited by 352 publications

References 32 publications

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK₂ receptors

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

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In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

Cited by 352 publications

References 32 publications

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice

Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK2 receptors

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

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Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK₂ receptors