We have previously suggested that activation of the hypothalamic-pituitary-adrenal (HPA) axis is dependent on cyclooxygenase (COX)-2-related signaling under infectious and restraint stresses, but less dependent on it under hypoglycemic stress. In the present study, we evaluated the neuronal activity in the brain to elucidate the possible mechanisms underlying a stress-specific relevance between COX-2-related signaling and activation of the HPA axis under infectious (lipopolysaccharide, LPS), hypoglycemic (2-deoxy-D-glucose, 2DG) and restraint (1 hr) stress conditions. The number of c-Fos-immunoreactive (IR) cells in several brain regions including the paraventricular nucleus (PVN) and supraoptic nucleus (SON) was increased at 120 min after application of all stress stimuli. The number of c-Fos-IR cells at 30 min was increased only by 2DG in the SON, but not in the PVN. In the PVN, a selective COX-2 inhibitor (NS-398) did not affect the number of c-Fos-IR cells at any time points. On the other hand, in the SON, NS-398 increased c-Fos-IR cells at 30 min after LPS and restraint stresses, but not after 2DG injection. These results suggest that, among the brain regions responding to acute stresses, the PVN and SON are commonly activated under three acute stresses. In addition, it is also suggested that COX-2-related signaling decreases neuronal activity in the SON under infectious and restraint, but not hypoglycemic, stresses, which may be involved in the suppression of the HPA axis.