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

Abstract

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]-2,4[1H,3H]-quinazolinedione tartrate]], 5-HT_2C [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-3,5-dichlorobenzoate]], 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-HT_1B (GR 55562), 5-HT_2A (ketanserin), 5-HT_2C (RS 102221), 5-HT₃ (MDL 72222), and 5-HT₄ (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 (α-methyl-5-hydroxytryptamine maleate), 5-HT_2C [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.