Cyclooxygenase-2-related signaling in the hypothalamus plays differential roles in response to various acute stresses

We previously suggested that cyclooxygenase (COX)-2 plays a role as a common mediator of stresses in the brain. In the present study, we evaluated the possible involvement of COX-2-related signaling in the activation of the hypothalamic–pituitary–adrenal (HPA) axis under three different stress conditions, namely infectious (lipopolysaccharide, LPS), hypoglycemic (2-deoxy-d-glucose, 2DG) and restraint (1 h) stresses in rats. Both an unselective COX inhibitor (indomethacin) and a selective COX-2 inhibitor (NS-398) significantly attenuated the increase of serum corticosterone levels after LPS and restraint stresses, but not after 2DG injection. COX-2 and microsomal prostaglandin E synthase (mPGES)-1 mRNA levels in the hypothalamus were significantly increased after LPS injection in intact rats. In adrenalectomized (ADX) rats, the expression of both genes was significantly increased after 2DG and restraint stresses, which was blocked by treatment with corticosterone. Interleukin-1β (IL-1β) mRNA levels in the hypothalamus in intact rats were increased only by LPS injection, though those in ADX rats were increased by all three stress stimuli. These results suggest that the relationship between COX-2-related signaling and activation of the HPA axis is stress–specific, and that COX-2-related signaling preferably mediates infectious and restraint stresses. Furthermore, the expression of COX-2 and mPGES-1 mRNA under the infectious stress condition was not negatively regulated by endogenous glucocorticoids, likely due to an increase in IL-1β levels.

► Infectious (LPS), hypoglycemic (2DG) and restraint stresses were applied. ► COX-2-related signaling mediates LPS and restraint, but not 2DG, stress stimuli. ► Glucocorticoids blunt COX-2-related signaling under 2DG and restraint stresses. ► Hypothalamic IL-1β mediates up-regulation of COX-2-related signaling by LPS.