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 mechanism by which Clostridium difficile toxin A causes substance P (SP) release and subsequent inflammation in the rat ileum is unknown. Pretreatment with the vanilloid receptor subtype 1 (VR1) antagonist, capsazepine, before toxin A administration significantly inhibited toxin A-induced SP release and intestinal inflammation. Intraluminal administration of the VR1 agonist capsaicin caused intestinal inflammation similar to the effects of toxin A. Pretreatment with capsazepine before capsaicin administration also significantly inhibited capsaicin-induced intestinal inflammation. These results suggest that intraluminal toxin A causes SP release from primary sensory neurons via stimulation of VR1 receptors resulting in intestinal inflammation.
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PMID:The capsaicin VR1 receptor mediates substance P release in toxin A-induced enteritis in rats. 1151 26

The rat L5/6 facet joint is innervated from L1 to L6 by the dorsal root ganglia (DRG). The presence of substance P- and calcitonin gene-related peptide-immunoreactive (ir) DRG neurons innervating the L5/6 facet joint has been demonstrated. However, the presence of brain-derived neurotrophic factor (BDNF)-ir and the vanilloid receptor subtype 1 (VR1)-ir DRG neurons, which relate to inflammatory and burning pain innervating the L5/6 facet joint, has not. Fluoro-gold (FG)-labeled neurons innervating the L5/6 facet joint were distributed throughout the DRGs from T13 to L6 levels. Of the FG-labeled neurons, the proportions of BDNF-ir in L1, L2, L3, L4 and L5 DRG neurons were 9%, 15%, 21%, 17% and 20% and the proportions of VR1-ir L1, L2, L3, L4 and L5 DRG neurons were 8%, 9%, 15%, 16% and 15%, respectively.
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PMID:Brain-derived neurotrophic factor and vanilloid receptor subtype 1 immunoreactive sensory DRG neurons innervating the lumbar facet joints in rats. 1177 2

The cloned capsaicin receptor, also known as vanilloid receptor subtype 1 (VR1) receptor, has been demonstrated to be an integral membrane protein with homology to a family of putative store-operated calcium channels. The VR1 receptor is activated not only by capsaicin but also by noxious heat and protons, and therefore it is suggested as a molecular integrator of chemical and physical stimuli that elicit pain. In the present study, indirect immunofluorescence detected a small number of neurons that are VR1 receptor immunoreactive (ir) (171 versus 1038 or 16% of all neuronal cell bodies) in the human trigeminal ganglion (TG). In addition, RT-PCR confirmed the presence of VR1 mRNA in the human TG. It has been hypothesized that TG neuronal cell bodies are the source of capsaicin-stimulated release of calcitonin gene-related peptide (CGRP), and hence co-localization experiments were performed. Around 10% of the VR1 receptor-ir is expressed on neurons that contain CGRP-ir (ten among 74) in the human TG, indicating that capsaicin may act through the VR1 receptor to modulate the release of CGRP and in turn to modulate pain. We observed that 8% of the VR1 receptor-ir neuronal cell bodies contain substance P-ir and 5% nitric oxide synthase. Capsaicin can release nitric oxide, CGRP and substance P from sensory nerves and contribute to central sensitization.
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PMID:Capsaicin receptor immunoreactivity in the human trigeminal ganglion. 1227 Jun 33

Intraluminal administration of the endocannabinoids N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) causes inflammation similar to that caused by Clostridium difficile toxin A in the rat ileum. The effects of anandamide and 2-AG were significantly inhibited by pretreatment with the specific capsaicin receptor (vanilloid receptor subtype 1; VR1) antagonist capsazepine. Pretreatment with the CB1 and CB2 cannabinoid receptor antagonists N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716) and N-[1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) did not affect the responses to anandamide. It has previously been shown that intraluminal toxin A stimulates substance P (SP) release from primary sensory neurons and that pretreatment with SP receptor [neurokinin (NK)-1 receptor] antagonists inhibits the inflammatory effects of toxin A. Anandamide stimulated SP release and this was blocked by capsazepine pretreatment. Also, pretreatment with the specific NK-1 receptor antagonist (2S,3S)-3-([3,5-bis[trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060) significantly inhibited the inflammatory effects of both toxin A and anandamide. Toxin A increased tissue concentrations of anandamide and 2-AG in the ileum, and these effects were enhanced after pretreatment with inhibitors of fatty acid amide hydrolase, a major endocannabinoid-degrading enzyme. The toxin A-stimulated release of anandamide but not 2-AG was selective over their congeners. These results demonstrate that the endocannabinoids anandamide and 2-AG stimulate intestinal primary sensory neurons via the capsaicin VR1 receptor to release SP, resulting in enteritis, and that endocannabinoids may mediate the inflammatory effects of toxin A.
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PMID:Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). 1253 26

The characteristics of the different populations of sensory nerve terminals that selectively contact pulmonary neuroepithelial bodies (NEBs) in rat lungs were investigated after chemical denervation with capsaicin and compared with control lungs. Vagal calbindin D28k and P2X(3) purinoceptor immunoreactive (IR) afferent nerve terminals contacting NEBs appeared to have their origin in the nodose ganglion. Thick CB/P2X(3)-IR nerve fibers were seen to be myelinated and to lose their myelin sheaths just before branching and protruding intraepithelially between the NEB cells. This vagal sensory component of the innervation of NEBs was not affected by capsaicin nor expressed capsaicin receptors (vanilloid receptor subtype 1). A second sensory nerve fiber population that selectively innervates pulmonary NEBs in the rat lung consists of thin unmyelinated nonvagal substance P/calcitonin gene-related peptide IR nerve fibers, contacting mainly the basal pole of pulmonary NEBs, and having their origin in dorsal root ganglia. In concordance with vanilloid receptor 1 expression on these nerve terminals, the spinal sensory substance P/calcitionin gene-related peptide-IR component of the innervation of NEBs was depleted by systemic capsaicin treatment. The complex sensory innervation pattern of pulmonary NEBs characterized in the present study strongly suggests that, physiologically, pulmonary NEBs represent a group of intraepithelial receptors that may be able to accommodate various local and central reflex actions, in relation to both chemo- and mechanosensory stimuli.
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PMID:Dual sensory innervation of pulmonary neuroepithelial bodies. 1259 50

The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non-selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series (n = 26) of normal (n = 7), diseased (n = 13) [prurigo nodularis (PN) (n = 10), generalized pruritus (n = 1), and mastocytosis (n = 2)], and capsaicin-treated human skin (n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase-polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation.
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PMID:Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. 1498 52

Endomorphin-2 (EM2) is a tetrapeptide with remarkable affinity and selectivity for the mu-opioid receptor. In the present study, we used double-fluorescence and electron microscopic immunocytochemistry to identify subsets of EM2-expressing neurons in dorsal root ganglia and spinal cord dorsal horn of adult rats. Within the lumbar dorsal root ganglia, we found EM2 immunoreactivity mainly in small-to-medium size neurons, most of which co-expressed the neuropeptide substance P (SP). In adult rat L4 dorsal root ganglia, 23.9% of neuronal profiles contained EM2 immunoreactivity and ranged in size from 15 to 36 microM in diameter (mean 24.3 +/- 4.3 microM). Double-labelling experiments with cytochemical markers of dorsal root ganglia neurons showed that approximately 95% of EM2-immunoreactive cell bodies also label with SP antisera, 83% co-express vanilloid receptor subtype 1/capsaicin receptor, and 17% label with isolectin B4, a marker of non-peptide nociceptors. Importantly, EM2 immunostaining persisted in mice with a deletion of the preprotachykinin-A gene that encodes SP. In the lumbar spinal cord dorsal horn, EM2 expression was concentrated in presumptive primary afferent terminals in laminae I and outer II. At the ultrastructural level, electron microscopic double-labelling showed co-localization of EM2 and SP in dense core vesicles of lumbar superficial dorsal horn synaptic terminals. Finally, 2 weeks after sciatic nerve axotomy we observed a greater than 50% reduction in EM2 immunoreactivity in the superficial dorsal horn. We suggest that the very strong anatomical relationship between primary afferent nociceptors that express SP and EM2 underlies an EM2 regulation of SP release via mu-opioid autoreceptors.
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PMID:Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat. 1507 52

Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic/diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.
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PMID:Capsaicin sensitive-sensory nerves and blood pressure regulation. 1532 Jun 97

Immunoreactivity for vanilloid receptor subtype 1 (VR1) and its analogue vanilloid receptor-like protein 1 (VRL1) were examined in combination with immunoreactivity for substance P (SP) and calcitonin gene-related peptide (CGRP) in the rat larynx. VR1 and VRL1 immunoreactivity were observed in the intraepithelial free nerve endings, subepithelial nerve plexus and laryngeal epithelial cells. Most of VR1 immunoreactive nerves were also immunoreactive for SP or CGRP. VR1 immunoreactive intraepithelial nerve endings may be laryngeal nociceptors.
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PMID:Immunolocalization of VR1 and VRL1 in rat larynx. 1562 May 71

Immunohistochemistry for substance P, somatostatin and vanilloid receptor subtype 1 as well as receptors for somatostatin and opioids was performed on the trigeminal ganglion in wild-type and Brn-3a knockout mice at postnatal day 0. In wild-type mice, the trigeminal ganglion contained abundant substance P-, vanilloid receptor subtype 1-, sst2A receptor- and delta-opioid receptor-immunoreactive neurons, while the ganglion had only a few mu-opioid receptor-immunoreactive neurons. The Brn-3a deficiency had an effect on the cell size but not the number of substance P-immunoreactive neurons. In knockout mice, the proportion of small immunoreactive neurons markedly increased and that of medium- to large-sized immunoreactive ones correspondingly decreased (mean +/- S.D. = 54.7 +/- 29.1 microm2, range = 10.9-220.8 microm2) compared to wild-type mice (mean +/- S.D. = 116.6 +/- 58.6 microm2, range = 27.3-400.7 microm2). As for vanilloid receptor subtype 1-immunoreactive neurons, the number and cell size was barely affected by the deficiency. On the other hand, the loss of Brn-3a caused a decrease in the number of sst2A receptor- or delta-opioid receptor-immunoreactive neurons (more than 95% reduction) and an increase in the number of mu-opioid receptor-immunoreactive neurons (9.3-fold increase). Somatostatin-immunoreactive neurons were not detected in the trigeminal ganglion of wild-type or mutant mice at postnatal day 0. The present study suggests that Brn-3a deficiency may have effects on the survival of trigeminal nociceptors and their expression of some neurochemical substances.
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PMID:Effect of Brn-3a deficiency on primary nociceptors in the trigeminal ganglion. 1574 Aug 7


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