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Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-β Signaling, Not μ-Opioid Receptor Internalization.
Molecular Pharmacology ( IF 3.6 ) Pub Date : 2020-10-01 , DOI: 10.1124/mol.120.119552
S Puig 1 , K E Barker 1 , S R Szott 1 , P T Kann 1 , J S Morris 1 , H B Gutstein 2
Affiliation  

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of μ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this view has also been called into question. We recently discovered that the platelet-derived growth factor receptor(PDGFR)-β signaling system is both necessary and sufficient to cause opioid tolerance. We therefore propose a completely new hypothesis: that opioid tolerance is mediated by selective cellular signals and is independent of MOR internalization. To test this hypothesis, we developed an automated software-based method to perform unbiased analyses of opioid-induced MOR internalization in the rat substantia gelatinosa. We induced tolerance with either morphine, which did not cause MOR internalization, or fentanyl, which did. We also blocked tolerance by administering morphine or fentanyl with the PDGFR-β inhibitor imatinib. We found that imatinib blocked tolerance without altering receptor internalization induced by either morphine or fentanyl. We also showed that imatinib blocked tolerance to other clinically used opioids. Our findings indicate that opioid tolerance is not dependent upon MOR internalization and support the novel hypothesis that opioid tolerance is mediated by intracellular signaling that can be selectively targeted. This suggests the exciting possibility that undesirable opioid side effects can be selectively eliminated, dramatically improving the safety and efficacy of opioids.

中文翻译:

脊髓阿片类药物耐受性取决于血小板衍生的生长因子受体-β 信号传导,而不是 μ-阿片受体内化。

阿片类药物是一些最有效的镇痛药。然而,它们的有效性受到镇痛耐受性发展的限制。传统上,耐受被认为是通过脱敏和内化终止μ-阿片受体 (MOR) 信号传导而发生的。矛盾的发现导致了最近的一项提议,即持续的 MOR 信号导致镇痛耐受。然而,这一观点也受到了质疑。我们最近发现血小板衍生生长因子受体(PDGFR)信号系统是引起阿片类药物耐受的必要和充分条件。因此,我们提出了一个全新的假设:阿片类药物耐受性由选择性细胞信号介导,并且与 MOR 内化无关。为了验证这一假设,我们开发了一种基于软件的自动化方法,对大鼠明胶中阿片类药物诱导的 MOR 内化进行无偏分析。我们使用不会引起 MOR 内化的吗啡或会引起 MOR 内化的芬太尼诱导耐受。我们还通过使用含有 PDGFR- β 的吗啡或芬太尼来阻断耐受性抑制剂伊马替尼。我们发现伊马替尼阻断耐受性而不改变由吗啡或芬太尼诱导的受体内化。我们还表明伊马替尼阻断了对其他临床使用的阿片类药物的耐受性。我们的研究结果表明,阿片类药物耐受性不依赖于 MOR 内化,并支持阿片类药物耐受性由可选择性靶向的细胞内信号传导介导的新假设。这表明可以选择性地消除不良阿片类药物副作用的令人兴奋的可能性,从而显着提高阿片类药物的安全性和有效性。
更新日期:2020-09-21
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