Expression of neural RGS-R7 and Gbeta5 Proteins in Response to Acute and Chronic Morphine.
The R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11), and its binding protein Gbeta5, are found in neural structures of mouse brain. A single intracerebroventricular priming dose of 10 nmol morphine gave rise to acute tolerance to the analgesic effects of successive identical test doses of the opioid. At 2 h after administering the acute opioid, RGS7 mRNA levels in the striatum plus those of RGS9-2 in the striatum and thalamus were increased, whereas RGS9-2 and RGS11 mRNA were reduced in the cortex. Similar but attenuated RGS-R7 mRNA changes persisted 24 h after acute morphine administration. No changes in Gbeta5 mRNA levels were observed. At 2 days after commencing sustained morphine treatment, the levels of mRNA for RGS7, RGS9-2, RGS11, and Gbeta5 increased in most of the brain structures studied (striatum, thalamus, periaqueductal gray matter (PAG), and cortex). In these morphine tolerant-dependent mice, the greater changes were found for RGS9-2 in the thalamus (>500%) and PAG (>200%). In post-dependent mice, the increases in RGS-R7 and Gbeta5 mRNA still persisted in the PAG and striatum at 8 and 16 days after starting the chronic opioid treatment. The raised mRNA levels promoted by chronic, but not by acute, morphine, were accompanied by increases in the encoded proteins. This is probably a result of the costabilization of the RGS-R7 and Gbeta5 proteins forming heterodimers. Opioid-induced adaptations of RGS-R7 and Gbeta5 genes may regulate the severity of morphine-induced tolerance/dependence and the duration of the post-dependent period, helping to recover the normal response.
López-Fando
Almudena
A
Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, CSIC, Madrid, Spain.
Rodríguez-Muñoz
María
M
Sánchez-Blázquez
Pilar
P
Garzón
Javier
J
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D004343:Drug Implants; D004361:Drug Tolerance; D004591:Electrophoresis, Polyacrylamide Gel; D044387:GTP-Binding Protein beta Subunits / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D020710:RGS Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017450:Receptors, Opioid, mu / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004343:Drug Implants; D044387:GTP-Binding Protein beta Subunits; C094668:Gnb5 protein, mouse; D009294:Narcotics; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C492038:Rgs7 protein, mouse; D009020:Morphine