ABSTRACT
Capsaicin, the pungent component of hot peppers, and the venom of the spider Phoneutria nigriventer are able to activate sensory nerves resulting in cutaneous neurogenic plasma extravasation. This study was undertaken to compare the ability of these substances to evoke oedema in the rat hind-paw and mechanisms underlying this effect. Subplantar injection of either Phoneutria nigriventer venom (PNV; 1-100 microg/paw) or capsaicin (10-200 microg/paw) caused a significant paw oedema that was potentiated by CGRP (10 pmol/paw). In rats treated neonatally with capsaicin to deplete neuropeptides, the paw oedema induced by either PNV (100 microg/paw) or capsaicin (100 microg/paw) was partially reduced (P<0.05). The tachykinin NK1 receptor antagonist SR140333 (0.2 micromol/kg; i.v.) prevented the paw oedema induced by the tachykinin NK1 receptor agonist GR73632 (30 pmol/paw) and partially reduced paw oedema induced by PNV or capsaicin. Treatment of rats with compound 48/80 (5 mg/kg; s.c. 3 days) or with both H1 receptor antagonist (mepyramine; 1 nmol/paw) and 5-HT receptor antagonist (methysergide; 1 nmol/paw) significantly inhibited PNV- or capsaicin-induced paw oedema. The combined treatment with mepyramine and methysergide and SR140333 further reduced PNV- and capsaicin-induced paw oedema. The bradykinin B2 receptor antagonist Hoe 140 affected neither PNV- nor capsaicin-induced responses. Our results suggest that PNV and capsaicin each induce paw oedema that is partially mediated by activation of sensory fibers culminating in the release of substance P as well as by activation of mast cells which in turn release amines such as histamine and 5-HT.
Subject(s)
Capsaicin/toxicity , Edema/chemically induced , Spider Venoms/toxicity , Animals , Animals, Newborn , Calcitonin Gene-Related Peptide/pharmacology , Capillary Permeability/drug effects , Edema/pathology , Female , Foot/innervation , Foot/pathology , Histamine H1 Antagonists/pharmacology , Indicators and Reagents , Male , Mast Cells/drug effects , Mast Cells/physiology , Neurokinin-1 Receptor Antagonists , Neurons, Afferent/drug effects , Piperidines/pharmacology , Quinuclidines/pharmacology , Rats , Rats, Wistar , p-Methoxy-N-methylphenethylamine/pharmacologyABSTRACT
1. The contribution of sensory neurons and mast cells to the oedema evoked by adenosine A1 (N(6)-cyclopentyladenosine, CPA, 3 - 30 nmol site(-1)), A2 (5'N-ethylcarboxamidoadenosine, NECA, 1 - 10 nmol site(-1)) and A3 receptor agonists (N6-[3-iodobenzyl]-N-methyl-5'-carboxiamidoadenosine, IB-MECA, 0.01 - 3 nmol site(-1)) was investigated in the rat skin microvasculature, by the extravascular accumulation of intravenously-injected (i.v.) 125I-albumin. 2. Intradermal (i.d.) injection of adenosine and analogues induced increased microvascular permeability in a dose-dependent manner (IB-MECA > NECA > CPA > adenosine). The non-selective adenosine receptor antagonist theophylline (5 - 50 nmol site(-1)) markedly inhibited adenosine, CPA or NECA but not IB-MECA-induced plasma extravasation. The A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.3 - 3 micromol kg(-1), i.v.) significantly reduced CPA-induced plasma extravasation whereas responses to adenosine, NECA or IB-MECA were unchanged. The A2 receptor antagonist 3,7-dymethyl-1-proprargylxanthine (DMPX, 0.5 - 50 nmol site(-1)) significantly reduced NECA-induced plasma extravasation without affecting responses to adenosine, CPA and IB-MECA. 3. The 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), but not the NK2 receptor antagonist (S)-N-methyl-N[4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]-benzamide (SR48968), significantly inhibited the plasma extravasation evoked by higher doses of adenosine (100 nmol site(-1)), CPA (100 nmol site(-1)), NECA (1 nmol site(-1)) and IB-MECA (0.1 - 1 nmol site(-1)). In rats treated with capsaicin to destroy sensory neurons, the response to higher doses of adenosine, CPA and NECA, but not IB-MECA, was significantly inhibited. 4. The effects of adenosine and analogues were largely inhibited by histamine and 5-hydroxytryptamine (5-HT) antagonists and by compound 48/80 pretreatment. 5. In conclusion, our results provide evidence that adenosine A1 and A2, but not A3, receptor agonists may function as cutaneous neurogenic pro-inflammatory mediators; acting via microvascular permeability-increasing mechanisms that can, depending on dose of agonist and purine receptor under study, involve the tachykinin NK1 receptor and mast cell amines.