Phoneutria nigriventer venom causes stimulation of capsaicin-sensitive primary afferent neurons in the rat dorsal skin, leading to neurogenic plasma protein extravasation due to the release of tachykinin NK1 receptor agonist. In this study we further investigated the mechanisms involved in the venom-induced activation of capsaicin-sensitive primary afferent neurons. The plasma extravasation in response to venom intradermally injected was measured in Wistar rats as the local accumulation of i.v. injected I-125-labelled human serum albumin into skin sites. The tachykinin NK1 receptor agonist, D-Ala-[L-Pro(9),Me-Leu(8)]substance P-(7-11) (GR73632; 10-100 pmol/site), induced a significant plasma leakage that was abolished by the selective tachykinin NK1 receptor antagonist, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333; 1 nmol/site), whereas the leakage after venom (1-10 mu g/site) was significantly inhibited (but not abolished) by SR140333. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37), failed to further reduce the residual plasma extravasation induced by venom plus SR140333, The mu-opioid receptor agonist, [D-Ala(2),Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO), and the local anaesthetic, Lignocaine, had no effect on the venom-induced plasma extravasation. Similarly, the L-, N- and P/Q-type voltage-sensitive Ca2+ channel blockers (verapamil, omega-conotoxin MVIIA and MVIIC, respectively) as well as the Na+ channel blockers, tetrodotoxin and carbamazepine, had no effect on the venom-induced effect. Neither the systemic treatment nor the local injection of ruthenium red prevented the venom-induced plasma extravasation. However, the vanilloid receptor antagonist, N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 120 mu mol/kg, i.v.), reduced by 48% (P <0.05) the venom (10 mu g/site)-induced plasma extravasation. A significant inhibitory effect was also observed with the P, purinoceptor agonists, adenosine 5'-triphosphate (ATP; 10 and 30 nmol/site) and adenosine 5'-diphosphate (ADP; 10 nmol/site). The involvement of histamine and/or 5-hydroxytryptamine (5-HT) in the venom-induced plasma extravasation was ruled out since neither histamine and 5-HT receptor antagonists nor depletion of mast cells by compound 48/80 affected the venom response. This was further supported by the failure of venom to degranulate in vitro peritoneal mast cells. In conclusion, only vanilloid receptors and P, prejunctional purinoceptors had an inhibitory effect on the neurogenic plasma extravasation evoked by P. nigriventer venom in rat dorsal skin. (C) 2000 Published by Elsevier Science B.V. All rights reserved.3913305315