RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Gαz subunits

Abstract

Two consecutive icv administrations of analgesic doses of mu-opioid receptor agonists lead to a profound desensitisation of the latter receptors; a third dose produced less than 20% of the effect obtained with the first administration. Desensitisation was still effective 24 h later. Impairing the activity of Gαz but not Gαi2 subunits prevented tolerance developing after the administration of three consecutive doses of morphine. Further, the icv injection of Gαi2 subunits potentiated morphine analgesia and abolished acute tolerance, whereas icv-administered Gαz subunits produced a rapid and robust loss of the response to morphine. The RGSZ1 and RGSZ2 proteins selectively deactivate GαzGTP subunits, and their knockdown increased the effects produced by the first dose of morphine. However, impairing their activity also accelerated tachyphylaxis following successive doses of morphine, and facilitated the development of acute morphine tolerance. In contrast, inhibiting the RGS9-2 proteins, which bind to GαoGTP and GαiGTP but only weakly deactivates them, preserved the effects of consecutive morphine doses and abolished the generation of acute tolerance. Therefore, desensitisation of mu-opioid receptors can be achieved by reducing the responsiveness of post-receptor elements (via the possible action of activated Gαz subunits) and/or by depleting the pool of receptor-regulated G proteins that agonists need to propagate their effects, e.g., through the activity of RGS9-2 proteins.