RGSZ1 and GAIP regulate mu- but not delta-opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance.
In the CNS, the regulators of G-protein signaling (RGS) proteins belonging to the Rz subfamily, RGS19 (G(alpha) interacting protein (GAIP)) and RGS20 (Z1), control the activity of opioid agonists at mu but not at delta receptors. Rz proteins show high selectivity in deactivating G(alpha)z-GTP subunits. After reducing the expression of RGSZ1 with antisense oligodeoxynucleotides (ODN), the supraspinal antinociception produced by morphine, heroin, DAMGO ([D-Ala2, N-MePhe4,Gly-ol5]-enkephalin), and endomorphin-1 was notably increased. No change was observed in the effect of endomorphin-2. This agrees with the proposed existence of different mu receptors for the endomorphins. The activities of DPDPE ([D-Pen2,5]-enkephalin) and [D-Ala2] deltorphin II, agonists at delta receptors, were also unchanged. Knockdown of GAIP and of the GAIP interacting protein C-terminus (GIPC) led to changes in agonist effects at mu but not at delta receptors. The impairment of RGSZ1 extended the duration of morphine analgesia by at least 1 h beyond that observed in control animals. CTOP (Cys2, Tyr3, Orn5, Pen7-amide) antagonized morphine analgesia when given during the period in which the effect of morphine was enhanced by RGSZ1 knockdown. Thus, in naive mice, morphine tachyphylaxis originated in the presence of the opioid agonist and during the analgesia time course. The knockdown of RGSZ1 facilitated the development of tolerance to a single dose of morphine and accelerated tolerance to continuous delivery of the opioid. These results indicate that mu but not delta receptors are linked to Rz regulation. The mu receptor-mediated activation of Gz proteins is effective at recruiting the adaptive mechanisms leading to the development of opioid desensitization.
Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, CSIC, Madrid, Spain. jgarzon@cajal.csic.es
Javier
J
Garzón
María
M
Rodríguez-Muñoz
Almudena
A
López-Fando
Antonio
A
García-España
Pilar
P
Sánchez-Blázquez
D048868:Adaptor Proteins, Signal Transducing; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000009:adverse effects / Q000737:chemistry / Q000502:physiology*; D002490:Central Nervous System / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000145:classification / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000009:adverse effects / Q000737:chemistry / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D020710:RGS Proteins / Q000009:adverse effects / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013618:Tachyphylaxis / Q000502:physiology*; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000701:Analgesics, Opioid; D002352:Carrier Proteins; C115271:Gipc1 protein, mouse; D009479:Neuropeptides; D020319:Oligodeoxyribonucleotides, Antisense; D020710:RGS Proteins; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D011993:Recombinant Fusion Proteins; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D013004:Somatostatin; D019204:GTP-Binding Proteins