Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes.

Interleukin-1 (IL-1) induces hypophagia, which can be reduced by cyclooxygenase (COX) inhibitors. Earlier studies with COX knockout (COXko) mice suggested that COX2 was more important for hypophagia than COX1. However, behavioral responses occur long before COX2 is induced. Hypophagia was assessed in mice by measuring the intake of sweetened milk in a brief period. The intake was reduced within 30 min after intraperitoneal injection of IL-1beta and was depressed for about 2 h. When milk intake was measured 30 to 40 min after IL-1beta, COX1ko mice showed an attenuated response, whereas COX2ko mice responded more like wild-type animals. By contrast, 90 to 120 min after IL-1beta COX1ko mice responded normally, whereas COX2ko mice showed only small responses. The COX2-selective inhibitor, celecoxib, failed to alter the response to IL-1beta 30 min after administration, but low doses antagonized the effects of IL-1beta at 90 to 120 min. The COX1-selective inhibitor, SC560, attenuated both the early and late responses, but a larger effect at 30 min than at 90 min suggested a role for COX1 at the earlier time. These results suggest that shortly after IL-1beta administration, COX1 is the major enzyme involved in the reduction of milk intake, whereas at later times COX2 is more important, paralleling its induction. Celecoxib also attenuated the milk intake response observed 2 h after lipopolysaccharide (LPS), and the reductions of food pellet intake and body weight induced by IL-1beta and LPS in the subsequent 24 h, suggesting that the role of COX2 may be more significant biologically than that of COX1.