The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on body temperature. WIN 55212-2 (1, 2.5, 5, and 10 mg/kg, i.m.) induced hypothermia in a dose-dependent manner. The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective CB(1) antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (5 and 10 mg/kg, i.m.), blocked the WIN 55212-2-induced hypothermia, suggesting that CB(1) receptor activation mediated the hypothermia. In contrast, the selective CB(2) antagonist, SR144528 [N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide)] (5 mg/kg, i.m.), did not alter the WIN 55212-2-induced hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 microg/microl) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 microg/microl), indicating that CB(1) receptors in the POAH mediated the hypothermia. The present results confirm the idea that CB(1) receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that 1) the POAH is the central locus for thermoregulation, and 2) CB(1) receptors within the POAH are the primary mediators of cannabinoid-induced hypothermia.