Endomorphin-1 is a selective endogenous ligand for the micro-opioid receptor, and this study investigated the effect of endomorphin-1 on rat knee joint inflammation by examining the ability of the neuropeptide to modulate synovial protein extravasation. Acute joint inflammation was induced by intraarticular injection of 2% kaolin followed by 2% carrageenan and the animals allowed to recover for 3 h. Immunohistochemical examination of these inflamed joints revealed endomorphin-1-like immunoreactive nerves in deep synovium with a proportion of the nerve fibers occurring in close proximity to synovial blood vessels. Perfusion of inflamed knees with exogenous endomorphin-1 across the dose range 10-9-10-6 M produced a significant reduction in synovial vascular permeability with the 10-7M dose producing the greatest fall in protein exudation (approx 55%). These effects were blocked by the specific micro-opioid receptor antagonist CTOP. Destruction of knee joint unmyelinated afferent nerve fibers by capsaicin treatment significantly attenuated the anti-inflammatory effects of endomorphin-1, suggesting that the peptide is acting via a neurogenic mechanism. The findings of this study indicate that endomorphin-1 acts peripherally in knee joints to reduce synovial protein extravasation. These anti-inflammatory effects are mediated by micro-opioid receptors located on capsaicin-sensitive afferent nerves.