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-HT(1A) WAY 100635 N-2-4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate salt]], 5-HT(1B) GR 55562 3-3-(dimethylamino)propyl]-4-hydroxy-N-4-(4-pyrid-dinyl)phenyl]benzamide dihydrochloride]], 5-HT(2A) ketanserin 3-2-4-(fluorobenzoyl)-1-piperidinyl]ethyl]-2,41H,3H]-quinazolinedione tartrate]], 5-HT(2C) RS 102221 8-5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro4.5]decane-2,4-dione hydrochloride]], 5-HT(3) MDL 72222 3-tropanyl-3,5-dichlorobenzoate]], and 5-HT(4) 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-HT(1B) (GR 55562), 5-HT(2A) (ketanserin), 5-HT(2C) (RS 102221), 5-HT(3) (MDL 72222), and 5-HT(4) (GR 113808) but not by 5-HT(1A) (WAY 100635) receptor antagonists. Topical administration of agonists of 5-HT(1A) (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide], 5-HT(1B) CGS 12066 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo-1,2-a]quinoxaline maleate salt]], 5-HT(2A) (alpha-methyl-5-hydroxytryptamine maleate), 5-HT(2C) MK 212 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride]], 5-HT(3) 1-(3-chlorophenyl)biguanide hydrochloride], and 5-HT(4) 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.