G_αi and G_βγ subunits have opposing effects on dexmedetomidine-induced sedation

Dexmedetomidine (DMED) is a potent and highly selective α₂-adrenergic receptor agonist and is widely used for short-term sedation. However, the mechanism of DMED-induced sedation has not been deciphered. In the present study, we investigated the mechanism of G_αi and G_βγ subunits on DMED-induced sedation. An ED₅₀ of DMED-induced loss of righting reflex (200.0nmol/kg) was increased to 375.0 or 433.3nmol/kg after pre-treatment with cAMP analog dbcAMP (50nmol/5 μl/mouse, i.c.v.) or the phosphodiesterase 4 inhibitor rolipram (100nmol/5 μl/mouse, i.c.v.). Conversely, the ED₅₀ of DMED-induced LORR decreased to 113.6 or 136.5 nmol/kg after pre-treated with G_βγ subunit inhibitor M119 (100 mg/kg, i.p.) or gallein (100 mg/kg, i.p.) respectively. Administration of dbcAMP, rolipram, gallein or M119 alone had no effect on LORR. Gallein (10 μM) significantly inhibited forskolin-stimulated cAMP accumulation in α_2A-AR -CHO cells. Compared with G_βγ subunit inhibitors or DMED alone, [Ca²⁺]i and pERK1/2 was significantly increased after co-administration with G_βγ subunit inhibitors and DMED. DbcAMP (5 μM) or rolipram (5 μM) alone had no effect on ERK1/2 phosphorylation, but decreased DMED-induced ERK1/2 phosphorylation after co-administration with DMED. G_βγ subunit inhibitor treatment increased DMED-induced phosphorylation of CREB, whereas dbcAMP or rolipram had no effect on pCREB induced by DMED. From our results we conclude that, G_βγ subunit may inhibit DMED-induced sedation through the cAMP and pERK1/2 pathway.