The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors.
Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in different neural structures by blocking their mRNA with antisense oligodeoxynucleotides (ODNs). This was achieved without noticeable changes in the binding characteristics of labeled beta-endorphin to opioid receptors. Knockdown of R7 proteins enhanced the potency of antinociception promoted by morphine and [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO)-both agonists at mu-opioid receptors. The duration of morphine analgesia was greatly increased in RGS9-2 and in RGS11 knockdown mice. The impairment of R7 proteins brought about different changes in the analgesic activity of selective delta agonists. Knockdown of RGS11 reduced [D-Ala(2)]deltorphin II analgesic effects. Those of RGS6 and RGS9-2 proteins caused [D-Ala(2)]deltorphin II to produce a smoothened time-course curve-the peak effect blunted and analgesia extended during the declining phase. RGS9-2 impairment also promoted a similar pattern of change for [D-Pen(2,5)]-enkephalin (DPDPE). RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects. A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals. Thus, R7 proteins play a critical role in agonist tachyphylaxis and acute tolerance at mu-opioid receptors, and show differences in their modulation of delta-opioid receptors.
Garzón
Javier
J
1Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, CSIC, Madrid, Spain. jgarzon@cajal.csic.es
López-Fando
Almudena
A
Sánchez-Blázquez
Pilar
P
D000818:Animals; D004361:Drug Tolerance / Q000502:physiology; D019204:GTP-Binding Proteins / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020710:RGS Proteins / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D013618:Tachyphylaxis / Q000502:physiology*
D016376:Oligonucleotides, Antisense; D020710:RGS Proteins; C492039:RGS7 protein, human; D017450:Receptors, Opioid, mu; C492038:Rgs7 protein, mouse; D019204:GTP-Binding Proteins