Src激酶抑制剂减轻吗啡耐受而不影响增加效应或精神运动刺激
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Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.
背景
延长的阿片类药物给药时间会导致以镇痛效力降低为特征的耐受性。阿片类药物产生的快感效应，也是其滥用的原因之一。多功能蛋白β-抑制蛋白2可调节吗啡的快感效应，也参与耐受性。这些行为可能通过减少内吞反应为μ阿片受体上调。β-抑制蛋白2还募集了μ受体的激酶。我们探讨了Src激酶对C57BL / 6小鼠的吗啡镇痛耐受性、运动刺激和强化效应中的作用。
方 法
我们比较了野生型、μ和β抑制蛋白2小鼠的吗啡镇痛作用（缩尾潜伏期，最大可能效应百分比，n=8-16只）、运动（行走距离，n=7-8只）和增强效应（条件位置偏好，n=7-8只）。并检测了c-Src抑制剂达沙替尼（n = 8）和PP2（n = 12）的影响。
结 果
使用吗啡的野生型小鼠的镇痛表现出耐受性，在第10天下降至最大可能效应的中值62％（四分位间距，29-92％）。接受达沙替尼的小鼠没有产生耐受性。μ小鼠的耐受性增强（34％最大可能效应;四分位数间距：第5天为5-52％）;达沙替尼（100％最大可能效应;四分位数间距：68-100％）和PP2（91％最大可能效应;四分位范围，78-100％）减弱小鼠的耐受性。相反，c-Src抑制剂不影响吗啡诱导的运动刺激和强化效应。值得注意的是，达沙替尼不仅减弱了耐受性，还逆转了μ小鼠已经产生的耐受性。
结 论
c-Src抑制剂减弱了耐受性从而恢复镇痛作用，且不改变吗啡的快感效应，使得c-Src抑制剂可能成为阿片类镇痛剂的辅助药。
原始文献摘要
Bull FA, Baptista-Hon DT, Sneddon C, Wright L, Walwyn W, Hales TG.Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.Anesthesiology. 2017 Nov;127(5):878-889. doi: 10.1097/ALN.0000000000001834.
Abstract
BACKGROUND:
Prolonged opioid administration leads to tolerance characterized by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein β-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect µ opioid receptor up-regulation through reduced endocytosis. β-Arrestin2 also recruits kinases to µ receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation, and reinforcement in C57BL/6 mice.
METHODS:
Analgesic (tail withdrawal latency; percentage of maximum possible effect, n = 8 to 16), locomotor (distance traveled, n = 7 to 8), and reinforcing (conditioned place preference, n = 7 to 8) effects of morphine were compared in wild-type, µ, µ, and β-arrestin2 mice. The influence of c-Src inhibitors dasatinib (n = 8) and PP2 (n = 12) was examined.
RESULTS:
Analgesia in morphine-treated wild-type mice exhibited tolerance, declining by day 10 to a median of 62% maximum possible effect (interquartile range, 29 to 92%). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in µ mice (34% maximum possible effect; interquartile range, 5 to 52% on day 5); dasatinib attenuated tolerance (100% maximum possible effect; interquartile range, 68 to 100%), as did PP2 (91% maximum possible effect; interquartile range, 78 to 100%). By contrast, c-Src inhibition affected neither morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance but also reversed established tolerance in µ mice.
CONCLUSIONS:
The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, makes c-Src inhibitors promising candidates as adjuncts to opioid analgesics.
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