Endomorphin-1 is a short chain neuropeptide with a high affinity for the µ-opioid receptor and has recently been localised in acutely inflamed knee joints where it was found to reduce inflammation. The present study examined the propensity of endomorphin-1 to modulate synovial blood flow in normal and adjuvant inflamed rat knee joints. Under deep urethane anaesthesia, endomorphin-1 was topically applied to exposed normal and 1 week adjuvant monoarthritic knee joints (0.1ml bolus; 10^-12 - 10^-9 mol). Relative changes in articular blood flow were measured by laser Doppler perfusion imaging and vascular resistances in response to the opioid were calculated. In normal knees, endomorphin-1 caused a dose-dependent increase in synovial vascular resistance and this effect was significantly inhibited by the specific µ-opioid receptor antagonist CTOP (P < 0.0001, 2 factor ANOVA, n = 5 - 7). One week following adjuvant inflammation, the hypoaemic effect of endormophin-1 was completely abolished (P < 0.0001, 2 factor ANOVA, n = 5 - 7). Immunohistochemical analysis of normal and adjuvant inflamed joints showed a 9-fold increase in endomorphin-1 levels in the monoarthritic knee compared to normal control. Western blotting and immunohistochemistry revealed a moderate number of µ-opioid receptors in normal knees, however, µ-opioid receptors were almost undetectable in arthritic joints. These findings demonstrate that peripheral administration of endomorphin-1 reduces knee joint blood flow and this effect is not sustainable during advanced inflammation. The loss of this hypoaemic response appears to be due to downregulation of µ-opioid receptors as a consequence of endomorphin-1 accumulation within the arthritic joint.