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

This short review examines two examples of studies into the mechanisms of allergic responses which have particular relevance to inflammation research. The first is the ability of human skin mast cells, but not those derived from lung, adenoids, tonsils or intestine, to release histamine in response to stimulation by neuropeptides including substance P, vasoactive intestinal polypeptide (VIP) and somatostatin. The neuropeptide activation site does not appear to be a classical tachykinin receptor but rather a binding site of low affinity and low specificity capable of interacting with neuropeptides and compounds with similar physicochemical characteristics. In contrast to IgE-dependent activation, neuropeptide stimulation of skin mast cells induces a rapid release of histamine with minimal generation of PGD2 and LTC4. This pseudo-allergic reaction is thought to underlie the weal and flare response in the skin and may have a role in urticaria. The second example describes studies to elucidate the mechanisms of the late asthmatic response by use of a guinea-pig model. As in man, both early and late phase responses in the guinea-pig are inhibited by sodium cromoglycate whereas only the early response is inhibited by the beta-adrenoceptor stimulant drug salbutamol. Examination of bronchoalveolar fluid has shown a temporal relationship between an airways neutrophilia and the late response. However, pharmacological manipulation and the use of an anti-neutrophil serum has shown that these events are not interdependent. The role of the airways eosinophilia requires further investigation.
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PMID:Allergy or inflammation? From neuropeptide stimulation of human skin mast cells to studies on the mechanism of the late asthmatic response. 265 5

1 Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% of maximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection of CGRP upon the response to SP although there was a tendency for an enhancement of the wheal response. 5 The H1-histamine antagonist terfenadine (60 mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered. 6. Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances. 7. These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo-oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NK, receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.
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PMID:Sensory neuropeptide effects in human skin. 289 55

There is good evidence that some vascular effects of inflammation in the skin are neurogenic and involve axon reflexes in the terminal arborizations of C-fibres containing substance P, neurokinin A and calcitonin gene-related peptide (CGRP). Substance P produces dose-related wheal and flare reactions in human skin. Neurokinin A induces wheal but little or no flare and is less potent than substance P. CGRP induces both wheal and flare but is also less potent than substance P. In addition, CGRP induces a slow-onset, intense vasodilatation in human skin which persists for several hours and is associated with leucocyte infiltration: a response which is not seen with substance P. Substance P also releases histamine from mast cells in the skin and the presence or absence of a role for histamine and mast cells in neurogenic inflammation in skin is discussed.
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PMID:The skin as an organ for the study of the pharmacology of neuropeptides. 307 45

A patient with solar urticaria induced by wavelengths 290-420 nm is reported. Wheals appeared after a few seconds of exposure to the sun; longer exposure caused general malaise and syncope. Intradermal injection of in vitro irradiated plasma caused a local whealing which was not seen with plasma kept dark. The wheals induced by irradiation could be inhibited by local injection of an antihistamine. Local injection of lidocaine and hydrocortisone was ineffective. Depletion of substance P in the skin by topical application of capsaicin did not change the sensitivity to irradiation with 313 nm and a single PUVA treatment did not change the minimal urticarial dose (MUD). Sunscreens were in practice of limited value with the exception of a protective plastic helmet. Repeated daily irradiation with UVA in increasing doses normalized his response to sunlight.
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PMID:Solar urticaria: mechanism and treatment. 374 56

1 Wheal and flare reactions are described following intradermal injections of somatostatin, vasoactive intestinal polypeptide, substance P and histamine in normal human forearm skin. Bombesin failed to produce a significant wheal and flare.2 Pretreatment of skin with capsaicin in all cases dramatically inhibited the flare but not the wheal. This result is in accord with the hypothesis that capsaicin blocks the effector side of the axon reflex, perhaps by depleting nerve terminals of vasodilatory peptide(s).
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PMID:Topical capsaicin pretreatment inhibits axon reflex vasodilatation caused by somatostatin and vasoactive intestinal polypeptide in human skin. 613 73

1 Substance P induced histamine release from rat peritoneal mast cells in a dose-dependent manner over the concentration range 1 to 10 microM. 2 At concentrations in the range 2.5 to 1 0 microM, neurotensin produced only about 5% release of histamine, which was substantially less than the maximum effect obtained with substance P. 3 Neurotensin, 2.5 to 10 microM produced graded inhibition of histamine release induced by substance P. The inhibitory effect of neurotensin was not seen when histamine release was induced by an antigen-antibody effect of neurotensin was not seen when histamine release was induced by an antigen-antibody reaction or by the ionophore, A 23187. Some evidence was obtained to suggest that compound 48/80 may interact with the same receptor as substance P and neurotensin. 4 [D-Arg8]neurotensin, [D-Arg9]neurotensin, xenopsin and the C-terminal octapeptide of substance P (SP4-11) all inhibited histamine release by substance P, but physalaemin did not. 5 Neurotensin inhibited the wheal and flare reactions induced by substance P in human skin. 6 [D-Trp7,9]substance P released histamine from rat mast cells and was about 12 times more potent than substance P itself. [D-Trp7,9]SP1-11 also produced wheal and flare responses in human skin, being 1.8 times more potent than substance P in the production of flare.
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PMID:Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. 618 39

The mechanism of cutaneous inflammation caused by substance P in human skin was assessed in five subjects receiving i.d. injections (5-405 pmol) at pH 7.2 as compared to histamine (0.08-1.6 nmol), compound 48/80 (100 ng) and solvent control. Both substance P and histamine produced sigmoid dose-response curves for the following parameters: 1 min and 5 min planimetrically measured areas of erythema, and mean diameter of weal. Substance P pretreatment induced tachyphylaxis, as assessed by standard methods with adequate controls, to both histamine and to substance P and vice versa. Erythema following substance P i.d. was not blocked by a constricting band. Diphenhydramine, and to a lesser extent doxantrazole, (but not cimetidine or indomethacin) when assessed as inhibitors after oral pretreatment, did shift dose response curves for histamine and substance P to the right. Light and electron microscopic assessment of mast cells was compared in substance P and solvent control injected human skin. These results support a possible role for substance P in cutaneous inflammation acting either directly or via histamine release from mast cells.
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PMID:Vascular responses of human skin to injection of substance P and mechanism of action. 618 19

Substance P (6.25-25 p-mole) produced dose-dependent flare and wheal responses when injected intradermally into the volar surface of the human forearm. The maximum flare response was obtained within the first 3 min of injection and declined thereafter. The wheal response reached a maximum after 12 min following the injection. Only those peptides having one or more basic residues in the N-terminal region were effective in producing a flare reaction. Eledoisin-related peptide and SP1-9 were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1-11 was twice as active. The N-terminal tetrapeptide, SP1-4 and eledoisin were inactive in the dose range tested. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin (2.0): [D-pro2, D-phe7, D-trp9]SP1-11 (1.1): SP1-11 (1.0): SP4-11 (0.4): SP1-9 (0.15): eledoisin-related peptide (0.08): eledoisin (0.06). The N-terminal tetrapeptide failed to produce a wheal response in the dose range tested. Substance P was approximately equi-active with poly-L-arginine in the production of wheal and flare and both of these agents were about 10 times more potent than histamine. Adenosine triphosphate (25-400 n-mole) produced dose-dependent wheal and flare responses and was 10,000 times less potent than substance P. Pre-treatment of the subjects with the H1 histamine antagonist, chlorpheniramine, (20 mg I.V.) reduced the wheal and flare responses to substance P. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine. The results are discussed in relation to the mechanism of the 'axon reflex' vasodilatation in skin. This is thought to involve mast cells in addition to substance P-containing primary afferent neurones.
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PMID:Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin. 619 37

(D-Pro4 D- Trp7 ,9,10)SP4-11 (SPA) has been shown to be a competitive antagonist of the histamine releasing action of substance P in rat peritoneal mast cells. Antagonist activity of SPA is expressed in the concentration range 1 to 10 microM, but at higher concentrations SPA releases histamine. SPA inhibits the flare response induced by substance P in human skin but is without effect on the wheal response. Up to 12.5 pmol SPA produces neither wheal nor flare response by itself. The structurally related peptide, kassinin , does not cause histamine release from rat mast cells at concentrations up to 10 microM whereas the methyl ester of substance P was found to 1.6 times more active than substance P in this respect. The findings are discussed in terms of the classification of substance P receptors and the mechanism of wheal and flare in human skin.
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PMID:The substance P receptor on rat mast cells and in human skin. 620 62

Recent data have shown both synergistic and inhibitory effects between calcitonin gene-related peptide (CGRP) and substance P (SP) on inflammation and flare responses. The modulatory effects of CGRP on the itch, flare and weal responses following intracutaneous injections of SP and histamine were studied in 10 healthy volunteers. The only change in itch responsiveness observed was a significant prolongation of itch latency following SP when preceded 10 min earlier by a CGRP injection. No influence on flare and weal was observed.
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PMID:Influence of calcitonin gene-related peptide on histamine- and substance P-induced itch, flare and weal in humans. 750 47


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