Normal rat and human synovium is innervated by small diameter, unmyelinated, peptide-containing nerves. A close anatomical association between these nerves and mast cells has been postulated23, although functional interactions have not been described. Capsaicin is frequently used to activate sensory nerves and we have examined both acute and long-term effects of capsaicin on passive synovial anaphylaxis (PSA) and blood flow in the rat knee joint. The acute injection of capsaicin into the synovial space (330 nmol, 30 min prior to antigen) significantly inhibited plasma extravasation into the joint tissues (measured by accumulation of [125I]-human serum albumin) following PSA, and produced vasoconstriction in normal joints (measured by 133Xe clearance). There was no effect on plasma extravasation when capsaicin was injected 3 h prior to antigen. Inhibition of the PSA response following acute intra-articular capsaicin was not reversed by pretreatment with the cyclo-oxygenase inhibitor indomethacin (to inhibit thromboxane generation) or in rats chronically treated with guanethidine (to deplete noradrenaline from post-ganglionic sympathetic fibres). Further, a longer term pre-treatment of the joints with a single intra-articular injection of capsaicin (3.3 mumol) also attenuated plasma extravasation following induction of PSA 7 days later, and was accompanied by a non-significant decrease in joint blood flow. Plasma extravasation in response to compound 48/80, a non-immunological mediator of mast-cell degranulation, was not affected in joints treated with capsaicin 7 days previously.(ABSTRACT TRUNCATED AT 250 WORDS)