Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the NK1 receptor in airway contraction induced by electrical field stimulation (EFS) was evaluated by comparing the response in NK1 receptor knockout mice (NK1R-/-) with that of NK1 receptor wild-type controls (WT). A frequency/response curve on tracheas from NK1R-/- mice and NK1R WT littermates was constructed. After incubation with [3H]choline, [3H]acetylcholine release upon EFS was measured by high-performance liquid chromatography and liquid scintillation counting. The effects of atropine (1 x 10(-6) M), tetrodotoxin (1 x 10(-6) M) and a specific NK1R antagonist (SR140333, 1 x 10(-8) M) were studied, as well as the effects of substance P (1 x 10(-5) M) on precontracted tracheas. Upon EFS, NK1R-/- mice had a significant lower trachea contractility than the NK1R WT animals, accompanied with less [3H]acetylcholine release. Pretreatment with atropine or tetrodotoxin abolished the EFS-induced contraction in both strains. Pretreatment with the NK1R antagonist SR140333 significantly reduced the contractility in the NK1R WT but not in the NK1R-/- mice. Substance P caused a small contraction in both NK1R WT and NK1R-/- mice. Substance P induced a relaxation in precontracted tracheas in NK1R WT but not in NK1R-/- mice. The data presented here provide direct evidence that the NK1 receptor augments cholinergic neurotransmission in mouse trachea.
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PMID:Modulatory role of tachykinin NK1 receptor in cholinergic contraction of mouse trachea. 1257 Jan 1

Inflammation, trauma, or nerve injury may cause enduring hyperalgesia, an enhanced sensitivity to painful stimuli. Neurons in lamina I of the spinal dorsal horn that express the neurokinin 1 receptor for substance P mediate this abnormal pain sensitivity by an unknown cellular mechanism. We report that in these, but not in other nociceptive lamina I cells, neurokinin 1 receptor-activated signal transduction pathways and activation of low-threshold (T-type) voltage-gated calcium channels synergistically facilitate activity- and calcium-dependent long-term potentiation at synapses from nociceptive nerve fibers. Thereby, memory traces of painful events are retained.
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PMID:Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. 1259 94

In the stomach, the majority of substance P's effects are mediated by the activation of neurokinin-1 (NK1) receptors. The gastric cellular distribution of these receptors in Wistar and Sprague-Dawley rats was determined using immunocytochemistry. The localization of the NK1 receptors with respect to von Willebrand's factor, protein gene product 9.5, substance P, vasoactive intestinal peptide, and calcitonin gene-related peptide was also determined. Results show that NK1 receptor immunoreactivity was dependent on the duration of fixation. In corpus and antrum tissues that were fixed in 4% paraformaldehyde for 30 min, the presence of NK1 receptor immunoreactivity was demonstrated on nerve fibers throughout the stomach, on the surface and in the cytoplasm of myenteric cell bodies, on circular smooth muscle cells, and on vascular endothelial cells. This was observed in tissues from both rodent strains. Overnight fixation in the same fixative, however, demonstrated the presence of NK1 receptor immunoreactivity only on nerve fibers and cell bodies of the myenteric plexus, and on circular smooth muscle cells. In 30-min fixed tissues, the localization of NK1R immunoreactivity on vascular endothelial cells and nerve fibers was confirmed by co-localization with von Willebrand's factor and protein gene product 9.5 immunoreactivity, respectively. In both rodent strains, NK1 receptor immunoreactivity was co-localized with substance P immunoreactivity on nerve fibers of the longitudinal and circular muscle. In the Wistar rat, NK1 receptor immunoreactivity was co-localized with vasoactive intestinal peptide immunoreactivity or calcitonin gene-related peptide immunoreactivity throughout the stomach. However, in the Sprague-Dawley rat, NK1 receptor immunoreactivity was only co-localized with calcitonin gene-related peptide immunoreactivity in a minority of fibers of the circular muscle. The overall results of this study show that the antigenic epitopes of the NK1 receptor are sensitive to overfixation. When tissues were not overfixed, NK1 receptor immunoreactivity was distributed more extensively throughout the rat stomach than has been described previously. The results of this study provide the anatomical basis for many of the actions of substance P in the rat stomach.
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PMID:Cellular localization and distribution of neurokinin-1 receptors in the rat stomach. 1264 11

In order to examine the possibility that some actions of substance P may be mediated by a variant of the neurokinin-1 (NK-1) receptor, we isolated and sequenced the cDNA encoding a truncated NK-1 receptor from guinea-pig celiac ganglion and brain mRNA by two-step RT-PCR based on the 3'RACE method. The truncated NK-1 receptor sequence corresponded to a splice variant missing the final exon 5, and encoded a 311-amino acid protein that was truncated just after transmembrane domain 7, in an identical position to a truncated variant of the human NK-1 receptor. Thus, the truncated NK-1 receptor lacked the intracellular C-terminus sequence required for the phosphorylation and internalisation of the full-length NK-1 receptor. Using a sensitive one-step semi-quantitative RT-PCR assay, we detected mRNA for both the full length and truncated NK-1 receptors throughout the brain, spinal cord, sensory and autonomic ganglia, and viscera. Truncated NK-1 receptor mRNA was present in lower quantities than mRNA for the full-length NK-1R in all tissues. Highest levels of mRNA for the truncated NK-1 receptor were detected in coeliac ganglion, spinal cord, basal ganglia and hypothalamus. An antiserum to the N-terminus of the NK-1 receptor labelled dendrites of coeliac ganglion neurons that were not labelled with antisera to the C-terminus of the full length NK-1 receptor. These results show that a C-terminally truncated variant of the NK-1 receptor is likely to be widespread in central and peripheral nervous tissue. We predict that this receptor will mediate actions of substance P on neurons where immunohistochemical evidence for a full-length NK-1 receptor is lacking.
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PMID:Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system. 1265 13

Nociceptin/orphanin FQ (N/OFQ), nocistatin, and prepro-N/OFQ 160-187 (C-peptide) are all derived from the same precursor protein. We examine the pharmacological mechanisms of nocistatin- and C-peptide-induced pronociceptive responses in a novel algogenic-induced nociceptive flexion test in mice. The intraplantar (i.pl.) injection of nocistatin- and C-peptide induced pronociceptive responses in a range of 0.01 to 10 or 1 pmol, respectively, which showed 100- to 1000-fold less potent effects than the N/OFQ. The nociceptive effects of both peptides were not affected by 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-one (J-113397) (i.pl.), an N/OFQ receptor antagonist, indicating that they are mediated by a novel mechanism independent of activation of N/OFQ receptor. Like N/OFQ, nocistatin-induced nociception was abolished by i.pl. injection of pertussis toxin, phospholipase C inhibitor, or CP-99994, a neurokinin 1 receptor antagonist, indicating that nocistatin may elicit nociception through a substance P release from nociceptor endings via activation of Gi/o and phospholipase C. The nociception was abolished by neonatal pretreatment (s.c.) with capsaicin or by i.t. pretreatment with CP-99994, but not MK-801 (i.t.), an N-methyl-d-aspartate receptor antagonist. In contrast, C-peptide-induced nociception was attenuated by the pretreatment with antisense oligodeoxynucleotide for Galphas (i.t.) and with KT-5720 (i.pl.), a cyclic AMP-dependent protein kinase inhibitor, but not with pertussis toxin. The nociception was neither attenuated by neonatal capsaicin nor by i.t. injection with CP-99994, but it was attenuated by i.t. injection with MK-801. These results suggest that nocistatin and C-peptide derived from prepro-N/OFQ stimulate distinct nociceptive fibers through different in vivo signaling mechanisms.
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PMID:Nocistatin and prepro-nociceptin/orphanin FQ 160-187 cause nociception through activation of Gi/o in capsaicin-sensitive and of Gs in capsaicin-insensitive nociceptors, respectively. 1266 41

Exposure to ozone (O3) induces airway hyperresponsiveness mediated partly through the release of substance P (SP) from nerve terminals in the airway wall. Although substantial evidence suggests that SP is released by sensory nerves, SP is also present in neurons of airway ganglia. The purpose of this study was to investigate the role of intrinsic airway neurons in O3-enhanced airway responsiveness in ferret trachea. To remove the effects of sensory innervation, segments of ferret trachea were maintained in culture conditions for 24 h before in vitro exposure to 2 parts/million of O3 or air for 1 h. Sensory nerve depletion was confirmed by showing that capsaicin did not affect tracheal smooth muscle responsiveness to cholinergic agonist or contractility responses to electrical field stimulation (EFS). Contractions of isolated tracheal smooth muscle to EFS were significantly increased after in vitro O3 exposure, but the constrictor response to cholinergic agonist was not altered. Pretreatment with CP-99994, an antagonist of the neurokinin 1 receptor, attenuated the increased contraction to EFS after O3 exposure but had no effect in the air exposure group. The number of SP-positive neurons in longitudinal trunk ganglia, the extent of SP innervation to superficial muscular plexus nerve cell bodies, and SP nerve fiber density in tracheal smooth muscle all increased significantly after O3 exposure. The results show that release of SP from intrinsic airway neurons contributes to O3-enhanced tracheal smooth muscle responsiveness by facilitating acetylcholine release from cholinergic nerve terminals.
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PMID:Substance P released from intrinsic airway neurons contributes to ozone-enhanced airway hyperresponsiveness in ferret trachea. 1273 Jan 46

Substance P engages the T cell neurokinin 1 receptor (NK-1R) to enhance IFN-gamma production. NK-1R on T cells is inducible. We studied mechanisms regulating T cell NK-1R expression. Murine splenocytes were cultured for 4 h with or without rIL-12 or rIL-18. Both IL-12 and IL-18 induced splenic T cells to express NK-1R transcripts. Induction was blocked by actinomycin D, but not cycloheximide, suggesting that protein synthesis was not required for initiation of NK-1R gene transcription. Inhibition of T cell NF-kappa B activation or NF-kappa B nuclear translocation also blocked NK-1R transcription. IL-12 and IL-18 strongly induce NK-1R mRNA expression in splenocytes from Stat4(-/-) mice, suggesting that the Stat4 pathway was not required for the induction of NK-1R transcription. Splenic T cells exposed to IL-12 or IL-18 in the presence of IL-10 expressed no NK-1R mRNA. However, TGF beta did not prevent NK-1R mRNA expression. Thus, IL-12 and IL-18 induce T cells to express NK-1R through NF-kappa B activation. IL-10, a regulator of the Th1 response, blocks this activation. These data further suggest that SP and NK-1R, which promote IFN-gamma synthesis, are part of the Th1 pathway of immunity.
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PMID:IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells. 1273 44

Destruction of neurons in the superficial dorsal horn that express substance P receptor (NK-1R) has been reported to block development of behavioral hypersensitivity following peripheral sensitization of nociceptors. Baseline sensitivity was not altered in these rat models that assessed innate reflex responses (i.e. hind-paw withdrawal to thermal or mechanical stimulation). In the present study, we evaluated effects of intrathecal substance P-saporin (SP-sap), a toxin selective for cells expressing NK-1R, on operant escape responses of rats to thermal stimulation. For comparison, lick/guard reflex testing was performed. Injection of a modest dose (175 ng) of SP-sap into the lumbar subarachnoid space produced a partial loss of lamina I/II NK-1R-expressing dorsal horn neurons but did not affect NK-1R-expressing neurons in deeper laminae. Lick/guard responses to 0.3, 44 or 47 degrees C were not affected after SP-sap treatment, but escape responses to these temperatures were significantly attenuated. Three hours after application of mustard oil to the dorsal surface of both hind paws, escape from 44 degrees C was enhanced for controls but not SP-sap-treated rats. Lick/guard responses were enhanced by mustard oil for both SP-sap and control animals. Administration of morphine (1.0 mg/kg, s.c.) before testing decreased escape responding at 47 degrees C for both controls and SP-sap rats. Thus, partial loss of NK-1R-expressing neurons in the superficial dorsal horn attenuated thermal nociceptive sensitivity and prevented secondary hyperalgesia when studied with an operant algesia assay, in contrast to innate reflexes which were less sensitive to modification by intrathecal SP-sap.
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PMID:Intrathecal substance p-saporin attenuates operant escape from nociceptive thermal stimuli. 1276 83

Migraine headaches are often precipitated by stress and seem to involve neurogenic inflammation (NI) of the dura mater associated with the sensation of throbbing pain. Trigeminal nerve stimulation had been reported to activate rat dura mast cells and increase vascular permeability, effects inhibited by neonatal pretreatment with capsaicin implicating sensory neuropeptides, such as substance P (SP). The aim of the present study was to investigate NI, assessed by extravasation of 99-Technetium-gluceptate (99Tc-G), as well as the role of mast cells, SP and its receptor (NK-1R) in dura mater of mice in response to acute stress. Restraint stress for thirty min significantly increased 99Tc-G extravasation in the dura mater of C57BL mice. This effect was absent in W/W(v) mast cell-deficient mice and NK-1 receptor knockout mice (NK-1R-/-), but was unaltered in SP knockout mice (SP-/-). Acute restraint stress also resulted in increased dura mast cell activation in C57BL mice, but not in NK-1R-/- mice. These data demonstrate for the first time that acute stress triggers NI and mast cell activation in mouse dura mater through the activation of NK-1 receptors. The fact that SP-/- mice had intact vascular permeability response to stress indicates that some other NK-1 receptor agonist may substitute for SP. These results may help explain initial events in pathogenesis of stress-induced migraines.
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PMID:Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-1 receptor knockout mice. 1286 61

Ileal pouch-anal anastomosis (IPAA) is an excellent surgical option for patients with chronic ulcerative colitis (CUC) requiring colectomy; however, persistent episodes of ileal pouch inflammation, or pouchitis, may result in debilitating postoperative complications. Because considerable evidence implicates substance P (SP) as an inflammatory mediator of CUC, we investigated whether SP participates in the pathophysiology of pouchitis. With the use of a rat model of IPAA that we developed, we showed that ileal pouch MPO levels and neurokinin 1 receptor (NK-1R) protein expression by Western blot analysis were significantly elevated 28 days after IPAA surgery. In situ hybridization and immunohistochemistry showed that the increase in NK-1R protein expression was localized to the lamina propria and epithelia of pouch ileum. The intraperitoneal administration of the NK-1R antagonist (NK-1RA) CJ-12,255 for 4 days, starting on day 28, was effective in reducing MPO levels. Starting on day 28, animals with IPAA were given 5% dextran sulfate sodium (DSS) in their drinking water for 4 days, which caused histological and physical signs of clinical pouchitis concomitant with significant increases in ileal pouch MPO concentrations as well as NK-1R protein expression by Western blot analysis. In situ hybridization and immunohistochemistry showed that the increase in NK-1R protein expression was especially evident in crypt epithelia of pouch ileum. When the NK-1RA was administered 1 day before starting DSS and continued for the duration of DSS administration, the physical signs of clinical pouchitis and the rise in MPO were prevented. These data implicate SP in the pathophysiology of pouchitis and suggest that NK-1RA may be of therapeutic value in the management of clinical pouchitis.
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PMID:A neurokinin 1 receptor antagonist reduces an ongoing ileal pouch inflammation and the response to a subsequent inflammatory stimulus. 1289 26


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