The　present　study　examined　the　involvement　of　5-HT　in　the　ventrolateral　orbital　cortex　(VLO)　on　descending　antinociception　and　determined　which　subtypes　of　5-HT　receptors　mediated　this　effect.　This　study　focused　on　the　effects　of　5-HT　microinjection　in　the　VLO　of　lightly　anesthetized　male　rats　on　the　radiant　heat-evoked　tail　flick　(TF)　reflex,　as　well　as　the　influence　of　5-HT1A,　5-HT2,　5-HT3,　and　5-HT4　receptor　subtype　antagonists　on　the　effect　of　5-HT.　Results　showed　that　5-HT　microinjection　(2,　5,　10　mu　g,　in　0.5　mu　l)　into　the　VLO　depressed　the　TF　reflex　in　a　dose-dependent　manner.　Pretreatment　with　5-HT　receptor　antagonists　(1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]　piperazine　hydrobromide　(NAN-190),　cyproheptadine　hydrochloride　(CPT)　and　1-methyl-N-(8-methyl-8-azabicyclo[3.2.3]-oct-3-yl)-1H-indazole-3-carboxamide　maleate　salt　(LY-278,584)),　specific　for　5-HT1A,　5-HT2　and　5-HT3　receptors,　respectively,　partially　reversed　the　5-HT-evoked　inhibition.　In　contrast,　the　5-HT4　receptor　antagonist,　1-[2-[(methylsulfonyl)-amino]　ethyl]-4-piperidinyl]methyl1-methyl-1H-indole-3-carboxylate　(GR　113808),　had　no　effect　on　the　inhibition　of　5-HT.　Microinjections　of　NAN-190,　CPT　and　LY-278,584　alone　into　the　VLO　had　no　effect　on　the　TF　reflex.　These　results　suggest　that　5-HT1A,　5-HT2　and　5-HT3,　but　not　5-HT4　receptors,　are　involved　in　mediating　5-HT-induced　antinociception　in　the　VLO.　According　to　different　properties　and　distribution　patterns　of　the　5-HT　receptor　subtypes　on　neurons,　the　possible　mechanism　of　5-HT　activation　of　the　VLO-periaqueductal　gray　(PAG)　descending　antinociceptive　pathway　is　discussed.　(C)　2008　Published　by　Elsevier　Ltd　on　behalf　of　IBRO.