ANTIHISTAMINE ANTINOCICEPTION IS MEDIATED BY GI-PROTEIN ACTIVATION

öThe e¡ect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the K subunit of di¡erent Gi-proteins (anti-GiK1, anti-GiK2, anti-GiK3) on the antinociception induced by the H1-antihistamines was evaluated in the mouse hot-plate test. The administration of diphenhydramine (20 mg kg31 s.c.), pyrilamine (15 mg kg31 s.c.) and promethazine (6 mg kg31 s.c.) produced an increase of the pain threshold which peaked 15 min after injection. Pretreatment with anti-GiK1 (12.5 Wg per mouse i.c.v.), anti-GiK2 (25 Wg per mouse i.c.v.) and anti-GiK3 (25 Wg per mouse i.c.v.), administered 24 and 18 h before test, prevented the antihistamine-induced antinociception. At the highest e¡ective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modi¢ed spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest an important role played by the Gi-protein pathway in the transduction mechanism involved in the enhancement of the pain threshold produced by H1-antihistamines.