The plasma protein extravasation induced by adenosine and its analogues inthe rat dorsal skin: evidence for the involvement of capsaicin sensitive primary afferent neurones and mast cells

1 The contribution of sensory neurons and mast cells to the oedema evoked b y adenosine A(1) (N-6-cyclopentyladenosine, CPA, 3-30 nmol site(-1)), A(2) (5'N-ethylcarboxamidoadenosine, NECA, 1-10 nmol site(-1)) and A(3) 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 t he extravascular accumulation of intravenously-injected (i.v.) I-125-albumi n. 2 Intradermal (i.d.) injection of adenosine and analogues induced increased microvascular permeability in a dose-dependent manner (IB-MECA > NECA > CP A > adenosine). The nonselective adenosine receptor antagonist theophylline (5-50 nmol site(-1)) markedly inhibited adenosine, CPA or NECA but not IB- MECA-induced plasma extravasation. The A, receptor antagonist 1,3 -dipropyl -8-cyclopentylxanthine (DPCPX, 0.3-3 mu mol kg(-1), i.v.) significantly red uced CPA-induced plasma extravasation whereas responses to adenosine, NECA or IB-MECA were unchanged. The A2 receptor antagonist 3,7-dymethyl-1-propra rgylxanthine (DMPX, 0.5-50 nmol site(-1)) significantly reduced NECA-induce d 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 evoke d 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 histamin e and 5-hydroxytryptamine (5-HT) antagonists and by compound 48/80 pretreat ment. 5 In conclusion, our results provide evidence that adenosine A(1) and A(2), but not A(3), receptor agonists may function as cutaneous neurogenic pro-i nflammatory mediators, acting via microvascular permeability-increasing mec hanisms that can, depending on dose of agonist and purine receptor under st udy, involve the tachykinin NK1 receptor and mast cell amines.