1. In previous work, we identified a prolonged and intense hyperaemic response of rat sciatic endoneurial vasa nervorum produced by epineurial application of capsaicin. We postulated that this response, which was blocked by substance P (SP) or calcitonin gene-related peptide (CGRP) antagonists, was a result of local release of neuropeptides on the 'feeding' epineurial vascular plexus. 2. In the present study, we evaluated factors that might influence capsaicin-induced hyperaemia of the rat sciatic endoneurium as measured by hydrogen clearance: central afferent connections, the epineurial vascular plexus, the release of histamine and administration of opiates. 3. Interruption of central afferent connections by proximal nerve section or removal of the epineurial vascular plexus did not influence baseline endoneurial perfusion. Plexus removal, but not proximal section, prevented capsaicin hyperaemia. 4. The epineurial vascular plexus was desensitized to the effect of capsaicin by prior application of capsaicin. Capsaicin hyperaemia was also prevented by: topical treatment with Spantide II ((D-NicLys1,3-Pal3,D-Cl2Phe5,Asn6,D-Trp7,9,Nl e11) substance P) an SP antagonist, systemic pretreatment with a combination of H1 and H2 histamine receptor antagonists, systemic pretreatment with cromolyn sodium or systemic pretreatment with morphine. None of these pretreatments influenced baseline perfusion. When systemic morphine was given together with systemic naloxone, an opiate antagonist, capsaicin-induced hyperaemia was restored. 5. These findings indicate that the capsaicin hyperaemia of vasa nervorum is locally mediated, is independent of central afferent connections and is sensitive to a variety of interventions. It requires an intact epineurial plexus that 'feeds' endoneurial microvessels and the release of histamine by mast cells. Its inhibition by morphine suggests that there are local opiate receptors on epineurial perivascular peptidergic fibres.