RGS9 proteins facilitate acute tolerance to mu-opioid effects.
This paper reports that regulators of G-protein signalling (RGS) proteins modulate the timing and amplitude of opioid signals by a push-pull mechanism. This is achieved without noticeable changes in the binding properties of opioids, e.g. beta-endorphin to mu-opioid receptors. The expression of RGS proteins was reduced by blocking their mRNA with antisense oligodeoxynucleotides (ODN). Knock down of RGS2 or RGS3 diminished morphine and beta-endorphin analgesia, whereas that of RGS9 or RGS12 enhanced this activity. In mice with impaired RGS9, but not impaired RGS2, the potency and, in particular, the duration of opioid antinociception increased. Further, the animals did not exhibit acute tolerance generated by a single and efficacious dose of morphine, nor did they develop tolerance after a daily i.c.v. injection of the opioid for 4 days. In a model of sustained morphine treatment, the impairment of RGS9 proteins facilitated increases in the response to the delivered opioid. This was only effective for 2--3 h after the subcutaneous implantation of an oily morphine pellet; later, tolerance developed. To reduce the impact of the chronic morphine acting on opioid receptors, other RGS proteins presumably substitute the GTPase-activating function of RGS9 on morphine-activated G-alpha-GTP subunits. The desensitization of mu-opioid receptors appears to be a cell membrane-limited process facilitated by RGS9's sequestering of agonist-segregated G alpha subunits.
Garzón
J
J
Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, E-28002 Madrid, Spain. jgarzon@cajal.csic.es
Rodríguez-Díaz
M
M
López-Fando
A
A
Sánchez-Blázquez
P
P
D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry; D004343:Drug Implants; D020558:GTP Phosphohydrolases / Q000502:physiology; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D018390:Gene Targeting; D006160:Guanosine Triphosphate / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007276:Injections, Intraventricular; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009020:Morphine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology; D011485:Protein Binding; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013618:Tachyphylaxis / Q000502:physiology*; D001615:beta-Endorphin / Q000494:pharmacology*
D000701:Analgesics, Opioid; D004343:Drug Implants; D020690:GTPase-Activating Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D020710:RGS Proteins; C485898:RGS3 protein, human; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C105345:Rgs2 protein, mouse; C415085:Rgs3 protein, mouse; C116925:regulator of g-protein signaling 9; D001615:beta-Endorphin; D009020:Morphine; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins