Garzón Javier, López-Fando Almudena, Sánchez-Blázquez Pilar
1Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, CSIC, Madrid, Spain.
Neuropsychopharmacology. 2003 Nov;28(11):1983-90. doi: 10.1038/sj.npp.1300263.
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.
G蛋白信号调节因子（RGS）蛋白R7亚家族成员（RGS6、RGS7、RGS9-2和RGS11）存在于小鼠中枢神经系统中。通过用反义寡脱氧核苷酸（ODN）阻断其mRNA，这些蛋白在不同神经结构中的表达被有效降低。在此过程中，标记的β-内啡肽与阿片受体的结合特性没有明显变化。R7蛋白的敲低增强了吗啡和[D-Ala(2), N-MePhe(4), Gly-ol(5)]-脑啡肽（DAMGO，两者均为μ-阿片受体激动剂）促进的抗伤害感受效力。在RGS9-2和RGS11敲低的小鼠中，吗啡镇痛的持续时间大大延长。R7蛋白的损伤导致选择性δ激动剂的镇痛活性发生不同变化。RGS11的敲低降低了[D-Ala(2)]强啡肽II的镇痛作用。RGS6和RGS9-2蛋白的敲低使[D-Ala(2)]强啡肽II产生了平滑的时程曲线——峰值效应减弱，镇痛作用在下降阶段延长。RGS9-2的损伤也促进了[D-Pen(2,5)]-脑啡肽（DPDPE）出现类似的变化模式。RGS7缺陷小鼠对[D-Ala(2)]强啡肽II和DPDPE的镇痛作用反应增强。单次脑室内（i.c.v.）给予吗啡的ED(80)镇痛剂量可使对照小鼠产生急性耐受性，但在RGS6、RGS7、RGS9-2或RGS11敲低的动物中不会促进耐受性产生。因此，R7蛋白在μ-阿片受体激动剂快速耐受性和急性耐受性中起关键作用，并且在对δ-阿片受体的调节方面存在差异。
