Objective. To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E 2 (PGE 2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. Methods. Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE 2 , and HA was determined in culture media. Sulfated glycosaminogly-can (S-GAG) synthesis was evaluated in cartilage by 35 S incorporation. Results. Fluoxetine (0.3 g/ml, 1 g/ml, and 3 g/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1 (IL-1; 1 ng/ml) plus tumor necrosis factor (TNF; 30 ng/ml). Amitriptyline (0.3 g/ml, 1 g/ml, and 3 g/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 g/ml, 1 g/ml, and 3 g/ml) significantly (P < 0.05) inhibited PGE 2 release in the media of human synovial cells in the presence of IL-1 plus TNF, in a dose-dependent manner (up to 88% inhibition). Fluox-etine (0.3 g/ml, 1 g/ml, and 3 g/ml) and amitripty-line (1 g/ml and 3 g/ml) significantly (P < 0.05) inhibited PGE 2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitrip-tyline (0.3 g/ml, 1 g/ml, and 3 g/ml) also significantly (P < 0.05) inhibited HA production by human synovial cells in the presence of IL-1 plus TNF. Fluoxetine and amitriptyline (1 g/ml) partially reversed IL-1-induced inhibition of 35 S-GAG synthesis by human cartilage cultures (P < 0.05). Neither fluox-etine nor amitriptyline had a toxic effect on cells in the concentrations used. Conclusion. Inhibition of NO and PGE 2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, artic-ular inflammation, and joint damage.
