UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The airways of the genetically hypertensive rat (GH) are hyperinnervated by substance P-containing sensory nerves and exhibit reduced inflammatory responsiveness to substance P and to capsaicin. The present study measured tracheal inflammation to resiniferatoxin (1.0 microgram/kg i.v.), a capsaicin analogue, which lacks the hypotensive action of capsaicin itself, alone or after the neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) (50 mg/kg i.p.). The inflammatory response to resiniferatoxin alone was 50% lower in untreated GH than in control rats, a similar strain difference to that seen previously with capsaicin. Pre-treatment with TRIM had no effect on inflammation in either strain. Binding kinetics of the tachykinin NK(1) receptor antagonist [3H](S)-1-(2-[3-(3, 4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4- phenyl-l-azoniabicyclo[2,2,2,]octane chloride ([3H]SR140333)(0.125-16.0 nM) showed 50% reduction of B(max) in GH versus control tracheae (74+/-13 cf.165+/-26 fmol/mg protein). Our results indicate that the reduced neurogenic inflammatory responsiveness in GH rats can be attributed entirely to reduced tachykinin NK(1) receptor numbers.
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PMID:Reduced inflammation in genetically hypertensive rat airways is associated with reduced tachykinin NK(1) receptor numbers. 1091 43

Alpha-actinin (alpha-actinin-2) is a protein which links the NR1 and NR2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptors to the actin cytoskeleton. Because of the importance of NMDA receptors in modulating the function of the striatum, we have examined the localization of alpha-actinin-2 protein and mRNA in striatal neurons, and its biochemical interaction with NMDA receptor subunits present in the rat striatum. Using an alpha-actinin-2-specific antibody, we found intense immunoreactivity in the striatal neuropil and within striatal neurons that also expressed parvalbumin, calretinin and calbindin. Conversely, alpha-actinin-2 immunoreactivity was not detected in neurons expressing choline acetyltransferase and neuronal nitric oxide synthase. Dual-label in situ hybridization revealed that the highest expression of alpha-actinin-2 mRNA is in substance P-containing striatal projection neurons. The alpha-actinin-2 mRNA is also present in enkephalinergic projection neurons and interneurons expressing parvalbumin, choline acetyl transferase and the 67-kDa isoform of glutamic acid decarboxylase, but was not detected in somatostatin-expressing interneurons. Immunoprecipitation of membrane protein extracts showed that alpha-actinin-2 is present in heteromeric complexes of NMDA subunits, but is not associated with AMPA receptors in the striatum. A subunit-specific anti-NR1 antibody co-precipitated major fractions of NR2A and NR2B subunits, but only a minor fraction of striatal alpha-actinin-2. Conversely, alpha-actinin-2 antibody immunoprecipitated only modest fractions of striatal NR1, NR2A and NR2B subunits. These data demonstrate that alpha-actinin-2 is a very abundant striatal protein, but exhibits cellular specificity in its expression, with very high levels in substance-P-containing projection neurons, and very low levels in somatostatin and neuronal nitric oxide synthase interneurons. Despite the high expression of this protein in the striatum, only a minority of NMDA receptors are linked to alpha-actinin-2. This interaction may identify a subset of receptors with distinct anatomical and functional properties.
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PMID:alpha-actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. 1092 45

This study was conducted to determine the origin(s) of neuronal nitric oxide synthase-immunoreactive (NOS-IR) fibers within guinea pig atrial whole-mount preparations containing the cardiac ganglia. Intrinsic NOS-IR cardiac neurons exhibited choline acetyltransferase (ChAT) immunoreactivity, indicating that they were cholinergic as well as nitrergic. Comparison of control versus 72-hour explant culture preparations indicated that most of the nitrergic fibers within cardiac ganglia were extrinsic. The extrinsic NOS-IR fibers were not IR for ChAT (marker of preganglionic parasympathetic neurons), tyrosine hydroxylase (marker of catecholaminergic sympathetic postganglionic axons), or calcitonin gene-related peptide (CGRP) (marker of afferent fibers). Separate NOS-IR and ChAT-IR neurons were present within medullary regions containing the cardiovascular regulatory nuclei (nucleus ambiguus and dorsal motor nucleus of the vagus), but no cells were found that exhibited both NOS immunoreactivity and ChAT immunoreactivity. The small size and location of the medullary NOS-IR neurons suggested they were probably interneurons. Only an occasional sympathetic postganglionic cell in the stellate ganglion complex exhibited NOS immunoreactivity. NOS-IR cells were present in dorsal root ganglia (thoracic 1-5), but these typically also exhibited CGRP immunoreactivity. NOS-IR cells were also present in the nodose ganglia, but only some exhibited CGRP immunoreactivity. We concluded that virtually all the extrinsic NOS-IR nerve fibers represented an afferent fiber input that was separate from the substance P (SP)/CGRP-containing population of sensory fibers. Furthermore, much of this NOS innervation is probably derived from the nodose ganglia.
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PMID:Origin of neuronal nitric oxide synthase (NOS)-immunoreactive fibers in guinea pig parasympathetic cardiac ganglia. 1099 51

1. Little is known about the intrinsic enteric reflex pathways associated with migrating motor complex (MMC) formation. Acetylcholine (ACh) mediates the rapid component of the MMC, however a non-cholinergic component also exists. The present study investigated the possible role of endogenous tachykinins (TKs) in the formation of colonic MMCs and the relative roles of excitatory and inhibitory pathways. 2. MMCs were recorded from the circular muscle at four sites (proximal, proximal-mid, mid-distal and distal) along the mouse colon using force transducers. 3. The tachykinin (NK(1) and NK(2)) receptor antagonists SR-140 333 (250 nM) and SR-48 968 (250 nM) reduced the amplitude of MMCs at all recording sites, preferentially abolishing the long duration contraction. Residual MMCs were abolished by the subsequent addition of atropine (1 microM). 4. The neuronal nitric oxide synthase inhibitor, N(omega)nitro-L-arginine (L-NOARG, 100 microM), increased MMC amplitude in the distal region, whilst reducing the amplitude in the proximal region. In preparations where MMCs did not migrate to the distal colon, addition of L-NOARG resulted in the formation of MMCs. Subsequent addition of apamin (250 nM) or suramin (100 microM) further increased MMC amplitude in the distal region, whilst suramin increased MMC amplitude in the mid-distal region. Apamin but not suramin reduced MMC amplitude in the proximal region. Subsequent addition of SR-140 333 and SR-48 968 reduced MMC amplitude at all sites. Residual MMCs were abolished by atropine (1 microM). 5. In conclusion, TKs, ACh, nitric oxide (NO) and ATP are involved in the neural mechanisms underlying the formation of MMCs in the mouse colon. Tachykinins mediate the long duration component of the MMC via NK(1) and NK(2) receptors. Inhibitory pathways may be involved in determining whether MMCs are formed.
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PMID:Neural mechanisms underlying migrating motor complex formation in mouse isolated colon. 1115 1

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5 M HCl or saline. IG HCl caused many neurons in the NTS and some neurons in the AP to express c-fos mRNA. The NMDA glutamate receptor antagonist MK-801 (2 mg/kg), the NK(1) tachykinin receptor antagonist GR-205,171 (3 mg/kg) and the NK(2) receptor antagonist SR-144,190 (0.1 mg/kg) failed to significantly reduce the NTS response to IG HCl, whereas the triple combination of MK-801, GR-205,171 and SR-144,190 inhibited it by 45--50%. Only in rats that had been preexposed IG to HCl 48 h before the experiment was MK-801 alone able to depress the NTS response to IG HCl. In contrast, the c-fos mRNA response in the AP was significantly augmented by MK-801, an action that was prevented by coadministration of GR-205,171 plus SR-144,190. Inhibition of neuronal nitric oxide synthase with 7-nitroindazole (45 mg/kg) was without effect on the IG HCl-evoked c-fos mRNA expression in the NTS and AP. Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK(1) and NK(2) receptors cooperate in the vagal afferent input from the acid-threatened stomach to the NTS and participate in the processing of afferent input to the AP in a different and complex manner. These opposing interactions in the AP and NTS and the increase in NMDA receptor function in the NTS after a gastric acid insult are likely to have a bearing on the neuropharmacology of dyspepsia.
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PMID:Cooperation of NMDA and tachykinin NK(1) and NK(2) receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach. 1116 70

The role of inducible (iNOS) and neuronal nitric oxide (nNOS) synthases and of tachykinin NK1 receptors on the pathogenesis of cyclophosphamide (CYP)-induced cystitis was investigated, in rats. CYP-induced cystitis was characterized by large increases in bladder-protein plasma extravasation (PPE), increases in the urinary excretion of nitric oxide (NO) metabolites and histological evidences of urothelial damage, edema, extensive white blood cell infiltrates and vascular congestion of the bladder. The specific iNOS inhibitor, S-methylthiourea (MITU), produced marked inhibition (>90%) of CYP-induced increases in PPE associated with amelioration of tissue inflammatory changes. Treatment with 7-nitroindazole (7-NI; 20, 40 and 80 mg/kg), a selective nNOS inhibitor, did not significantly reduce CYP-induced increases in PPE and failed to produce histological improvement. In addition, treatment with MITU, but not with 7-NI, inhibited the increases in the urinary excretion of NO metabolites induced by CYP treatment. WIN 51,708 (17-beta-hydroxy-17-alpha-ethynyl-androstano[3,2-b]pyrimido[1,2-a]benzimidazole; WIN), a selective NK1-receptor antagonist, reduced the increases in EPP and ameliorated the inflammatory changes in the bladder induced by CYP. However, the maximal degree of protection achieved with WIN was significantly less than that produced by MITU. Combined treatment with the iNOS inhibitor and the NK1 antagonist produced no greater effect than that produced by the iNOS inhibitor alone. Our results suggest that NO plays a fundamental role in the production of the cystitis associated with CYP treatment. The iNOS, and not nNOS, seems responsible for the inflammatory changes. Part of the increases in NO may due to activation of NK1 receptors by neuropeptides such as substance P possibly released from primary afferent fibers.
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PMID:Nitric oxide synthases and cyclophosphamide-induced cystitis in rats. 1128 51

Endocrine cells containing somatostatin (Som), gastrin-releasing peptide (GRP), and neuronal nitric oxide synthase (nNOS) and nerve fibers containing choline acetyl transferase (ChAT), tyrosine hydroxylase (TH), galanin (Gal), substance P (SP), and vasoactive intestinal polypeptide (VIP) were immunolocalized in the proventriculus of the Houbara bustard, Chlamydotis undulata. While GRP-immunoreactive (GRP-IR) cells occur in the inner zone, somatostatin (Som-IR) and polyclonal nNOS (nNOS-IR) immunoreactive cells were localized mainly in the peripheral zone of submucosal glands. GRP-IR, Som-IR, and nNOS-IR cells were occasionally observed in the walls of the gastric glands. Endocrine cells are of the closed variety and usually possess apical processes extending along the basal surfaces of adjacent nonreactive cells. Ultrastructural features of these cells are typical. ChAT, Gal, SP, VIP, and TH were immunolocalized in nerve fibers and terminals in the walls of arterioles and capillaries at the periphery of submucosal glands. Immunoreactivity to monoclonal nNOS occurred mainly in neuronal cell bodies in ganglia located around the submucosal glands. ChAT and TH immunoreactive cell bodies were also occasionally seen around the submucosal glands in the peripheral region. Immunoreactivity to Gal, SP, and VIP, but not ChAT or TH, was discernible around the walls of gastric glands. It was concluded that the distribution of neurotransmitters in neuronal structures is similar, but that of the endocrine cells varies from that of some avian species. The roles of these neurotransmitters in the regulation of acid secretion are discussed.
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PMID:Neurotransmitters regulating acid secretion in the proventriculus of the Houbara bustard (Chlamydotis undulata): a morphological viewpoint. 1130 48

The indirect immunofluorescent method was employed to investigate the distribution of neuronal nitric oxide synthase-like immunoreactivity(nNOS-LI) in the spinal cord of the golden hamster and to compare it to data obtained from rats. Immunoreactive neurons were found throughout the cervico-sacral extent in the dorsal horn (mainly in laminae I-III) and in the preganglionic autonomic regions, i.e., the sympathetic intermediolateral nucleus (IML), lateral funicle (LF), intercalated region (IC), the area surrounding the central canal (CA), and the sacral preganglionic parasympathetic cell group. While the distribution of immunoreactive cells was generally similar in both species, some differences were observed. For example in the hamster LF, a higher percentage of stained neurons was seen than in the IML, while the situation was rather inverse in the rat. In order to study the coincidence of nNOS-LI in the population of preganglionic sympathetic neurons (PSN) that innervate the superior cervical ganglion (SCG), these were identified by retrograde axonal transport of fluoro-gold (FG) following unilateral injection into the SCG. PSN were localized ipsilateral to the injection site mainly in the IML and LF of spinal segments C7-Th4. The portion of double-labeled neurons of the IML were lower in hamster (17% in C7, 34% in C8) of FG-labeled cells) than in rat (47% in C8, 77% in Th2), while in the LF of segments C8-Th2 in both species the majority of FG-neurons contained nNOS. While only very few double-labeled neurons were detected in the IC in hamster and rat, a striking difference was observed in the CA, where no double-labeled neurons were found in hamster, but up to 50% in rat. Double immunofluorescence detection of nNOS and substance P (SP) showed that in both the autonomic regions and the dorsal horn, SP-LI fibers and puncta were present in close spatial relationship to nNOS-LI cell bodies. These results were basically identical in the hamster and rat. Unilateral transection of the dorsal roots of segments C6-Th2 in rats resulted in a clear reduction of SP-LI structures in the dorsal horn 5 days after rhizotomy, but not in the autonomic regions. Compared to the unlesioned side, the numbers of nNOS-LI neurons in the superficial laminae of the dorsal horn were reduced to 32-46% in the lesioned segments, and to 53% and 87%, respectively, in the two segments cranial to the rhizotomized segments but remained unchanged caudally to the lesion. Numbers of nNOS-LI cell bodies in the autonomic regions were not altered following dorsal root transection. The present study provides data on the widespread distribution of nNOS in the spinal cord of golden hamster and describes the partial coincidence of the enzyme in PSN. The effects of dorsal rhizotomy on nNOS-LI neurons in the dorsal horn reveal that primary-afferent fibers provide a stimulatory influence on neurons of the dorsal horn to generate the gaseous neuroactive substance, nitric oxide.
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PMID:Nitric oxide synthase neurons in the rodent spinal cord: distribution, relation to Substance P fibers, and effects of dorsal rhizotomy. 1131 59

Using a reversible chronic constriction injury (CCI) model of neuropathic pain, we previously demonstrated that changes in thermal hyperalgesia correlate with the changes in peripheral microvascular blood flow in the affected paw, and that recovery can be assessed by normalization of both behavioral and vascular responses. Using the same model, this study examined age-related changes in recovery after nerve injury and the involvement of free radicals and nitric oxide (NO) in these changes. Four loose, nonconstrictive ligatures were applied to the sciatic nerve in the right, mid-thigh region of young and old (3 and 24 months) Sprague Dawley rats. All rats were monitored weekly (for 8-10 weeks) for their thermal threshold using a 46 degrees C water bath and some groups were used to examine endothelial and smooth muscle-dependent microvascular responses to substance P (SP) and sodium nitroprusside (SNP), respectively. These substances were perfused over the base of blisters raised on the footpad innervated by the injured nerve. Free radical activity in the sciatic nerve was assessed by measuring the activity of xanthine oxidase (XO) and lipid hydroperoxides (LPO). Young rats showed signs of recovery (reduction in thermal hyperalgesia and improvement of peripheral microvascular blood flow) from the fifth week. No signs of recovery were observed in old rats for 8 weeks, with some reduction in thermal hyperalgesia observed by weeks 9 and 10. XO activity was significantly higher in young injured nerves compared to sham (400%) and was even significantly greater in old injured nerves (680%). Similarly, old injured nerves showed 300% increase in LPO levels compared to sham. The role of reactive oxygen species (ROS) in delayed recovery in old rats was examined using the antioxidant tirilazad mesylate. Tirilazad (20 mg/kg) was injected intramuscularly (im) in the mid-thigh region starting on day 1 post CCI, (early treatment) or day 7 (late treatment). Levels of LPO in the injured sciatic nerves were significantly reduced using either early or late treatment, however tirilazad had opposing effects on recovery, prolonging or alleviating thermal hyperalgesia, respectively. The role of neuronal nitric oxide (nNO) was then examined using the specific neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (3Br-7NI) (10 mg/kg). 3Br-7NI resulted in a significant alleviation of thermal hyperalgesia with improvement in the vascular responses from weeks 5 and 6 onwards. A combination of 3Br-7NI and tirilazad treatment was also used but did not show an additive effect. The results suggest that ROS and nNO contribute to delayed recovery of injured nerves in old rats and to the maintenance of thermal hyperalgesia and the reduction in microvascular blood flow in the area innervated by the injured nerve. The results also raise the notion that possible interaction of free radicals with NO to form peroxynitrite might be responsible for such delayed recovery. Ironically, this study also reveals a positive role for free radicals in tissue repair and raises the notion that early intervention with antioxidants could exert a negative effect on repair of injured nerves.
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PMID:A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. 1149 76

Interstitial cells of Cajal (ICC) are important regulatory cells in the smooth muscle coats of the digestive tract. Expression of the Kit receptor tyrosine kinase was used in this study as a marker to study their distribution and development in the striated musculature of the mouse esophagus. Sections and whole-mounts were studied by immunohistochemistry. KitW-lacZ transgenic mice, which carry the lacZ reporter gene inserted in place of the first exon of the Kit gene, were processed for Xgal histochemistry, for quantitative analysis and for ultrastructural studies. Spindle-shaped ICC were scarce in both muscle layers of the thoracic esophagus, while their number increased steeply toward the cardia in the striated portion of the intraabdominal esophagus. They did not form networks and had no relationship with intrinsic myenteric ganglia and motor end-plates. They were often close to nerve fibers immunoreactive for neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP) or neuropeptide Y (NPY), but not to fibers immunoreactive for substance P (SP), calcitonin gene related peptide (CGRP), enkephalin, or the capsaicin receptor VRI. They were present in the fetus but absent in adult ICC-deficient KitW-lacZ/KitWv mice. Interstitial cells of Cajal were identified by electron microscopy by their ultrastructure in the striated muscle of the esophagus and exhibited Xgal labeling, while fibroblasts and muscle cells were unlabeled. Interstitial cells of Cajal are scattered between striated muscle cells in the mouse esophagus. They are close to nerves with defined neurochemical coding and could possibly represent specialized esophageal spindle proprioceptors.
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PMID:Interstitial cells of Cajal in the striated musculature of the mouse esophagus. 1168 70

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