Deletion of guanine nucleotide binding protein α_z subunit in mice induces a gene dose dependent tolerance to morphine

The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G _z, a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G_z second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Gα_z knockout mouse develops significantly increased tolerance to morphine, which depends on Gα_z gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G_z signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.