RGS9 proteins facilitate acute tolerance to mu-opioid effects
RGS9 proteins facilitate acute tolerance to mu-opioid effects
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DOI：
10.1046/j.0953-816x.2000.01444.x
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发表时间：
2001-02-01
影响因子：
3.4
通讯作者：
Sánchez-Blázquez, P
中科院分区：
文献类型：
--
作者：
Garzón, J;Rodríguez-Díaz, M;Sánchez-Blázquez, P
本文报道了G蛋白信号(RGS)蛋白的调节剂通过推挽机制调节阿片信号的时序和幅度。这是在阿片类药物的结合性质没有明显变化的情况下实现的，例如β-内啡肽与Mu-阿片受体的结合。用反义寡核苷酸(ODN)封闭RGS蛋白的mRNA，使其表达降低。RGS2或RGS3可减弱吗啡和β-内啡肽的镇痛作用，而RGS9或RGS12可增强这一作用。在RGS9受损但RGS2未受损的小鼠中，阿片类抗伤害作用的效力和持续时间增加。此外，这些动物没有表现出单一有效剂量的吗啡产生的急性耐受性，也没有在每天静脉注射后产生耐受性。注射阿片类药物4天。在持续吗啡治疗的模型中，RGS9蛋白的损伤促进了对阿片类药物的反应增强。这只在皮下植入油性吗啡颗粒后2-3小时有效；后来，产生了耐受性。为了减少慢性吗啡对阿片受体的影响，其他RGS蛋白可能在吗啡激活的Gα-GTP亚基上替代了RGS9的GTP酶激活功能。Mu-阿片受体的脱敏可能是由RGS9‘S隔离激动剂分离的Gα亚基促进的细胞膜限制性过程。
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.