TIAPRIDE ATTENUATES PAIN TRANSMISSION THROUGH AN INDIRECT ACTIVATION OF CENTRAL SEROTONERGIC MECHANISM

Tiapride dose-dependently attenuated the biphasic nociceptive response s induced by s.c, injection of formalin to the hindpaw of mice, and it s activity on the first (ED(50) = 110 mg/kg p.o.) and the second (ED(5 0) = 32.0 mg/kg p.o,) phases paralleled that on the nociceptive respon se to intrathecal injection of substance P (ED(50) = 190 mg/kg p.o.) a nd somatostatin (ED(50) = 56.0 mg/kg p.o.), respectively, Moreover, a similar antinociceptive activity was observed in streptozotocin-induce d diabetic or genetically diabetic (db/db) mice. The effects of tiapri de (100 mg/kg p.o.) on both phases of the formalin test in normal mice were abolished by pretreatment with p-chlorophenylalanine (800 x 2 mg /kg p.o.), a 5-hydroxytryptamine (5-HT) depletor, or pindolol (1 mg/kg i.p.), a 5-HT1 antagonist, but were scarcely affected by 3-tropanyl-i ndole-3-carboxylate, a 5-HT3 antagonist. Ketanserin (1 mg/kg i.p.), a 5-HT2 antagonist, attenuated the effect of tiapride on the second phas e but not on the first phase. This study on the antinociceptive mechan ism of action of tiapride (that blocks painful neuropathy in diabetic patients) has led us to hypothesize that the drug attenuates pain tran smission through an indirect activation of central 5-HT1 and 5-HT2 rec eptors.