Garzón J, Rodríguez-Díaz M, López-Fando A, Sánchez-Blázquez P
Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, E-28002 Madrid, Spain.
Eur J Neurosci. 2001 Feb;13(4):801-11. doi: 10.1046/j.0953-816x.2000.01444.x.
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.
本文报道，G蛋白信号调节（RGS）蛋白通过一种推挽机制调节阿片类信号的时间和幅度。这一过程在阿片类药物（如β-内啡肽与μ-阿片受体）的结合特性没有明显变化的情况下实现。用反义寡脱氧核苷酸（ODN）阻断RGS蛋白的mRNA可降低其表达。敲低RGS2或RGS3可减弱吗啡和β-内啡肽的镇痛作用，而敲低RGS9或RGS12则增强这种活性。在RGS9功能受损但RGS2功能未受损的小鼠中，阿片类药物抗伤害感受的效力，特别是持续时间增加。此外，这些动物不会因单次有效剂量的吗啡产生急性耐受性，在每天脑室内注射阿片类药物4天后也不会产生耐受性。在持续吗啡治疗模型中，RGS9蛋白功能受损促进了对给予的阿片类药物反应的增强。这在皮下植入油性吗啡丸后仅2 - 3小时有效；之后，耐受性产生。为了减少慢性吗啡对阿片受体的影响，其他RGS蛋白可能替代了RGS9对吗啡激活的G-α-GTP亚基的GTP酶激活功能。μ-阿片受体的脱敏似乎是一个受细胞膜限制的过程，由RGS9对激动剂分离的Gα亚基的隔离作用所促进。
