The peripheral nervous system and its neuropeptidergic pathways may play an important role in the pathogenesis and development of rheumatoid arthritis. In the present study, the role of the neuropeptide somatostatin (SRIF), which was recently shown to be implicated in inflammatory diseases of the gastrointestinal tract, was evaluated by measuring the expression of somatostatin receptors in synovium from patients with rheumatoid arthritis. Somatostatin receptors were detected using in vitro receptor autoradiography in the synovium from five patients with active disease. No receptors were found in one case, a successfully treated patient with quiescent disease. The receptors were of high affinity and specific for biologically active somatostatin analogs. Displacement by nanomolar concentrations of somatostatin-14, somatostatin-28, and octreotide was observed, suggesting that most of the receptors identified belong to the SRIF1A subtype. The somatostatin receptors were preferentially located in blood vessels, with specific labeling of the veins but not of the arteries. The whole vessel wall was homogeneously labeled including the smooth muscle cells and probably the endothelium. These data suggest that the synovium in active rheumatoid arthritis expresses a high density of somatostatin receptors. Somatostatin may act through these venous receptors to influence the inflammatory process by induction of vasoconstriction, inhibition of plasma extravasation and cell migration, or inhibition of neovascularization.