We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local prostaglandin (PG)E₂ release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE₂ and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (₁-AR agonist) and clonidine (₂-AR agonist) into the POA of conscious guinea pigs pretreated intraPOA with SC-560 (COX-1 inhibitor), nimesulide or MK-0663 (COX-2 inhibitors), and measured the animals' core temperature (T_c) and intraPOA PGE₂ responses. Cirazoline induced T_c rises promptly after the onset of its dialysis without altering PGE₂ levels. NE and clonidine caused early falls followed by late rises of T_c; intraPOA PGE₂ levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine induced T_c and PGE₂ falls, but not the NE-elicited hyperthermia; but COX-2 inhibition suppressed both the clonidine- and NE-induced T_c and PGE₂ rises. Co-infused cirazoline and clonidine reproduced the late T_c rise of clonidine but not its early fall, and also not the early rise produced by cirazoline; on the other hand, the PGE₂ responses were similar to those to NE. Prazosin (₁-AR antagonist) and yohimbine (₂-AR antagonist) blocked the effects of their respective agonists. These results indicate that ₁- and ₂-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct T_c responses: ₁-AR activation produces quick, PGE₂-independent T_c rises, and ₂-AR stimulation causes an early T_c fall and a late, COX-2/PGE₂-dependent T_c rise.