Ruthenium red has recently been found to inhibit the effects of capsaicin on peripheral terminals of sensory neurones. Thus the effects of ruthenium red on the responses of the guinea-pig isolated ileum to capsaicin, acetylcholine (ACh), substance P (SP) and nicotine were investigated. Ruthenium red, 5 mumol/l, abolished responses to capsaicin 1.5 mumol/l and nicotine 2 mumol/l, and shifted the concentration-response lines to ACh and SP to the right. Pretreatment of ileum preparations with ruthenium red, 12.5 mumol/l for 2 min, prevented desensitization of ileum responses to capsaicin tested 30 min later. Tetrodotoxin, 1 mumol/l, abolished the response to capsaicin on control preparations and those pretreated with atropine, 5 mumol/l, ruthenium red, 12.5 mumol/l or spantide, 10 mumol/l. It is proposed that capsaicin acts via a specific receptor coupled to a receptor-operated membrane calcium channel, and that ruthenium red binds irreversibly to the calcium channel part of the complex but reversibly to some other site which prevents the action or binding of capsaicin at its specific receptor.