THE EFFECT OF A TACHYKININ NK1 RECEPTOR ANTAGONIST, SR140333, ON EDEMA FORMATION INDUCED IN RAT SKIN BY VENOM FROM THE PHONEUTRIA NIGRIVENTER SPIDER

1 The possibility that tachykinin NK1 receptors are involved in the pl asma extravasation evoked by intradermal (i.d.) injection of Phoneutri a nigriventer venom (PNV) in rat dorsal skin in vivo has been investig ated. 2 Local oedema formation induced by the i.d. injection of test a gents was measured by the extravascular accumulation of intravenously (i.v.) injected I-125-labelled human serum albumin over a 30 min perio d. 3 The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced l ocal oedema formation which was potentiated by co-injection with the n europeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmo l per site). The non-peptide tachykinin NK1 receptor antagonist, SR140 333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited ( 0.3 nmol per site, P < 0.05; 1 nmol per site, P < 0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histami ne (10 nmol per site) with CGRP. 4 PNV (0.03-0.3 mu g per site) inject ed i.d. induced dose-dependent local oedema formation. SR140333 (1 nmo l per site, co-injected i.d.) inhibited oedema formation; with complet e inhibition observed at doses of 0.03 mu g (P < 0.05) and 0.1 mu g (P < 0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 mu g (P < 0.05). 5 Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B-2 rece ptor antagonist, Hoe 140 (80 nmol kg(-1), i.v.), which was used at a d ose which significantly inhibited oedema formation by bradykinin (1 nm ol per site). 6 Local oedema formation induced by PNV was significantl y inhibited (P < 0.01) by co-injection of the histamine H-1 receptor a ntagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxy tryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7 In t he presence of all three antagonists (mepyramine 2.5 nmol per site; me thysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasm a extravasation induced by PNV was further significantly inhibited (P < 0.001, when compared with PNV injected i.d. alone; P < 0.05 when com pared with PNV co-injected with mepyramine and methysergide and P < 0. 01, when compared with PNV co-injected with SR140333). 8 These results suggest that oedema formation evoked by i.d. PNV in rat skin may be p artially mediated via a mechanism involving tachykinin NK1 receptors a nd that this effect is independent of histamine and 5-HT.