Roles of 5-hydroxytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats

5-Hydroxytryptamine ( 5-HT; serotonin) plays an important role in the descending control of nociception. 5-HT and its receptors have been extensively studied in the modulation of nociceptive transmission at the spinal level using behavioral tests that may be affected by the effects of 5-HT on motor performance and skin temperature. Using electrophysiological methods, the present study aimed to systematically investigate the roles of 5-HT receptor subtypes on the inhibitory effects of 5-HT on responses of the spinal wide dynamic range ( WDR) neurons to C-fiber inputs in rats. Under basal conditions, topical application of 5-HT to the spinal cord inhibited the C-fiber responses of WDR neurons dose-dependently, whereas antagonists of 5-HT1A [ WAY 100635 [ N-[ 2-[ 4( 2-methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate salt]], 5-HT1B [GR 55562 [ 3-[ 3-( dimethylamino) propyl]-4-hydroxy-N-[ 4-(4- pyrid-dinyl) phenyl] benzamide dihydrochloride]], 5-HT2A [ ketanserin [ 3-[ 2-[ 4-( fluorobenzoyl)-1-piperidinyl] ethyl]-2,4[ 1H, 3H]-quinazolinedione tartrate]], 5-HT2C [ RS 102221 [ 8-[ 5-( 2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido) phenyl-5-oxopentyl]-1,3,8-triazaspiro[ 4.5] decane-2,4-dione hydrochloride]], 5-HT3 [ MDL 72222 [ 3-tropanyl-3,5dichlorobenzoate]], and 5-HT4 [ GR 113808 ([ 1-[ 2-[( methylsulfonyl)amino] ethyl]-4-piperidinyl] methyl 1-methyl-1H-indole-3-carboxylate)] had no effect on their own. The inhibitory effects of 5- HT were reversed by antagonists of 5-HT1B ( GR 55562), 5-HT2A ( ketanserin), 5-HT2C ( RS 102221), 5-HT3 ( MDL 72222), and 5-HT4 ( GR 113808) but not by 5-HT1A ( WAY 100635) receptor antagonists. Topical administration of agonists of 5-HT1A [( 2R)-( +)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide], 5-HT1B [ CGS 12066 [ 7-trifluoromethyl-4-( 4-methyl-1-piperazinyl) pyrrolo[ 1,2- a] quinoxaline maleate salt]], 5-HT2A ( alpha-methyl-5-hydroxytryptamine maleate), 5-HT2C [ MK 212 [ 6-chloro-2-( 1- piperazinyl) pyrazine hydrochloride]], 5-HT3 [ 1-( 3-chlorophenyl) biguanide hydrochloride], and 5-HT4 [ 2-[ 1-( 4- piperonyl) piperazinyl] benzothiazole] also inhibited the C-responses. These results suggest that, under basal conditions, there is no tonic serotonergic inhibition on the C-responses of dorsal horn neurons, and multiple 5-HT receptor subtypes including 1B, 2A, 2C, 3, and 4 may be involved in mediating the inhibitory effects of 5- HT.