The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract
The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract
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DOI：
10.1124/jpet.111.186320
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Akbarali, Hamid I.
中科院分区：
文献类型：
--
作者：
Kang, Minho;Maguma, Hercules T.;Akbarali, Hamid I.
据报道，β - arrestin2在镇痛耐受性中起重要作用。镇痛耐受而不伴随便秘耐受是慢性吗啡治疗的限制性副作用。由于小鼠对吗啡的耐受性是在回肠而不是结肠中形成的，因此我们研究了β -arrestin2在回肠和结肠中吗啡耐受性机制中的作用是否不同。在豚鼠和小鼠中，长期体外暴露于吗啡（2小时，10 μ M）导致离体回肠产生耐受性，但结肠没有。吗啡暴露后豚鼠回肠纵肌肌丛电场刺激收缩抑制的IC50值由5.7 +/- 0.08 （n = 9）右移至5.45 +/- 0.09 (n = 6) （p < 0.001）。在结肠中未观察到明显的变化。在小鼠回肠和结肠之间也发现了类似的耐受性差异。然而，β -arrestin2基因敲除小鼠的结肠中产生了耐受性。Western blot检测豚鼠纵肌肌丛β - arrestin2和细胞外信号调节激酶1/2的表达水平。在吗啡（10 μ M）暴露2小时后，回肠出现β -arrestin2和细胞外信号调节激酶1/2表达的时间依赖性下降，而结肠没有。纳洛酮阻止了β -抑制素的下降。在豚鼠体内长期用吗啡治疗7天的离体回肠中，既没有出现对吗啡体外暴露的额外耐受性，也没有出现β -抑制蛋白2的减少。我们得出结论，β -arrestin2的减少与胃肠道对吗啡的耐受性发展有关。
beta-Arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant tolerance to constipation is a limiting side effect of chronic morphine treatment. Because tolerance to morphine develops in the mouse ileum but not the colon, we therefore examined whether the role of beta-arrestin2 in the mechanism of morphine tolerance differs in the ileum and colon. In both guinea pig and mouse, chronic in vitro exposure (2 h, 10 mu M) to morphine resulted in tolerance development in the isolated ileum but not the colon. The IC50 values for morphine-induced inhibition of electrical field stimulation contraction of guinea pig longitudinal muscle myenteric plexus shifted rightward in the ileum from 5.7 +/- 0.08 (n = 9) to 5.45 +/- 0.09 (n = 6) (p < 0.001) after morphine exposure. A significant shift was not observed in the colon. Similar differential tolerance was seen between the mouse ileum and the colon. However, tolerance developed in the colon from beta-arrestin2 knockout mice. beta-Arrestin2 and extracellular signal-regulated kinase 1/2 expression levels were determined further by Western blot analyses in guinea pig longitudinal muscle myenteric plexus. A time-dependent decrease in the expression of beta-arrestin2 and extracellular signal-regulated kinase 1/2 occurred in the ileum but not the colon after 2 h of morphine (10 mu M) exposure. Naloxone prevented the decrease in beta-arrestin2. In the isolated ileum from guinea pigs chronically treated in vivo with morphine for 7 days, neither additional tolerance to in vitro exposure of morphine nor a decrease in beta-arrestin2 occurred. We conclude that a decrease in beta-arrestin2 is associated with tolerance development to morphine in the gastrointestinal tract.