RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Galphaz subunits.
Two consecutive i.c.v. 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 24h later. Impairing the activity of Galphaz but not Galphai2 subunits prevented tolerance developing after the administration of three consecutive doses of morphine. Further, the i.c.v. injection of Galphai2 subunits potentiated morphine analgesia and abolished acute tolerance, whereas i.c.v.-administered Galphaz subunits produced a rapid and robust loss of the response to morphine. The RGSZ1 and RGSZ2 proteins selectively deactivate GalphazGTP 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 GalphaoGTP and GalphaiGTP 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 Galphaz 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.
Sánchez-Blázquez
Pilar
P
Neuropharmacology, Cajal Institute, CSIC, Dr Arce 37, E-28002 Madrid, Spain.
Rodríguez-Muñoz
María
M
Montero
Carlos
C
Garzón
Javier
J
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D005786:Gene Expression Regulation; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008954:Models, Biological; D009294:Narcotics / Q000008:administration & dosage; D020710:RGS Proteins / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013997:Time Factors
D005136:Eye Proteins; D044385:GTP-Binding Protein alpha Subunits; D009294:Narcotics; D020710:RGS Proteins; C107413:RGS16 protein; D017450:Receptors, Opioid, mu; C116925:regulator of g-protein signaling 9