Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS.
BACKGROUND
In cell culture systems, agonists can promote the phosphorylation and internalization of receptors coupled to G proteins (GPCR), leading to their desensitization. However, in the CNS opioid agonists promote a profound desensitization of their analgesic effects without diminishing the presence of their receptors in the neuronal membrane. Recent studies have indicated that CNS proteins of the RGS family, specific regulators of G protein signalling, may be involved in mu-opioid receptor desensitization in vivo.


OBJECTIVE
In this work we review the role played by RGS proteins in the intensity and duration of the effects of mu-opioid receptor agonists, and how they influence the delayed tolerance that develops in response to specific doses of opioids.


RESULTS
RGS proteins are GTPase-activating proteins (GAP) that accelerate the hydrolysis of GalphaGTP to terminate signalling at effectors. The GAP activity of RGS-R4 and RGS-Rz proteins restricts the amplitude of opioid analgesia, and the efficient deactivation of GalphazGTP subunits by RGS-Rz proteins prevents mu receptor desensitization. However, RGS-R7 proteins antagonize effectors by binding to and sequestering mu receptor-activated Galphai/o/z subunits. Thus, they reduce the pool of receptor-regulated G proteins and hence, the effects of agonists. The delayed tolerance observed following morphine administration correlates with the transfer of Galpha subunits from mu receptors to RGS-R7 proteins and the subsequent stabilization of this association.


CONCLUSIONS
In the CNS, the RGS proteins control the activity of mu opioid receptors through GAP-dependent (RGS-R4 and RGS-Rz) as well as by GAP-independent mechanisms (RGS-R7). As a result, they can both antagonize effectors and desensitize receptors under certain circumstances.
Garzón
Javier
J
Neurofarmacología, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Doctor Arce, 37, 28002, Madrid, Spain. jgarzon@cajal.csic.es
Rodríguez-Muñoz
María
M
de la Torre-Madrid
Elena
E
Sánchez-Blázquez
Pilar
P
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020555:GTP-Binding Protein Regulators / Q000502:physiology*; D044385:GTP-Binding Protein alpha Subunits / Q000502:physiology; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011957:Receptors, Opioid / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction
D000701:Analgesics, Opioid; D020555:GTP-Binding Protein Regulators; D044385:GTP-Binding Protein alpha Subunits; D020710:RGS Proteins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine