Structure‐activity relationships for some substance P‐related peptides that cause wheal and flare reactions in human skin.

Abstract

SUMMARY1. 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.2. 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.3. 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 , were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1 -1 was twice as active. The N-terminal tetrapeptide, SP1 4 and eledoisin were inactive in the dose range tested.4. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin ( response in the dose range tested.5. 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 H, histamine antagonist, chlorpheniramine, (20 mg i.v.) reduced the wheal and flare responses to substance P.6. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response.7. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine.8. 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.

Specific neurokinin receptors mediate plasma extravasation in the rat knee joint

“…Marked plasma extravasation can be elicited by direct administration of SP into the synovial cavity of rat knee (Lam & Ferrell, 1989a,b) which can be inhibited by pretreatment with substance P antagonist D-Pro4, D-Trp7'9"0 SP(4-11) (Lam & Ferrell, 1989a). The plasma extravasation induced by SP is thought to be mediated by interactions from the carboxyl terminus of the neuropeptide with specific vascular receptors (Foreman et al, 1983). An N-terminal analogue of SP as verified in human skin (Foreman et al, 1983) failed to induce plasma extravasation.…”

“…The plasma extravasation induced by SP is thought to be mediated by interactions from the carboxyl terminus of the neuropeptide with specific vascular receptors (Foreman et al, 1983). An N-terminal analogue of SP as verified in human skin (Foreman et al, 1983) failed to induce plasma extravasation. The common C-terminal of the tachykinins suggest that they should all induce plasma extravasation as was found to be the case in studies on rat skin (Brain & Williams, 1989;Andrews et al, 1989).…”

Characterization of neuropeptide‐induced histamine release from human dispersed skin mast cells

“…The ability of human skin mast cells to release histamine in response to substance P, VIP and somatostatin is consistent with in vivo findings in human skin where intradermal injection of each of these neuropeptides induces weal and flare reactions (Anand et al, 1983). The flare, or vasodilatory, component of such reactions is considered to be mediated by histamine, being inhibited by H1-histamine antagonists (Hagermark et al, 1978), is neurogenic, being inhibited by nerve section, prior application of local anaesthetics and depletion of peripheral nerve neuropeptide content by capsaicin (Bayliss, 1901;Foreman et al, 1983;Anand et al, 1983), and therefore is thought to involve an interaction between skin mast cells and neuropeptides (Hagermark et al, 1978;Foreman et al, 1983). Calcitonin gene-related peptide and neurotensin, which we have shown to be poor histamine releasers from human skin mast cells, are much less potent than substance P in inducing both weal and flare reactions in human skin and histamine release from rat peritoneal mast cells Piotrowski & Foreman, 1986).…”

“…There is some evidence that the ability of neuropeptides to induce weal and flare reactions in human skin is closely correlated to histamine releasing activity from rat peritoneal mast cells (Foreman et al, 1983). These cells release histamine in response to both IgE-dependent and non-immunological stimuli (Lagunoff et al, 1983).…”

Calcitonin gene‐related peptide is localised to human airway nerves and potently constricts human airway smooth muscle

“…The nerve fibres (arrows) are seen surrounding both immunoreactive ganglion cells (c) (magnification x 420). (Brain et al, 1985;Foreman et al, 1983;Barnes et al, 1986), the flare response to CGRP having a very long duration. SP has also been implicated in the pathogenesis of bronchial oedema and the response to irritants .…”