Anesthesiology Institute, Allegheny Health Network, Pittsburgh, Pennsylvania (H.B.G.); University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (S.P., S.R.S., P.T.K.); MD Anderson Cancer Center, Houston, Texas (K.E.B.); and Biostatistics Division, Perelman School of Medicine, Philadelphia, Pennsylvania (J.S.M.).
Anesthesiology Institute, Allegheny Health Network, Pittsburgh, Pennsylvania (H.B.G.); University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (S.P., S.R.S., P.T.K.); MD Anderson Cancer Center, Houston, Texas (K.E.B.); and Biostatistics Division, Perelman School of Medicine, Philadelphia, Pennsylvania (J.S.M.)
Mol Pharmacol. 2020 Oct;98(4):487-496. doi: 10.1124/mol.120.119552. Epub 2020 Jul 28.
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 -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)- 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- 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. SIGNIFICANCE STATEMENT: Classically, it was thought that analgesic tolerance to opioids was caused by desensitization and internalization of -opioid receptors (MORs). More recently, it was proposed that sustained, rather than reduced, MOR signaling caused tolerance. Here, we present conclusive evidence that opioid tolerance occurs independently of MOR internalization and that it is selectively mediated by platelet-derived growth factor receptor signaling. This novel hypothesis suggests that dangerous opioid side effects can be selectively targeted and blocked, improving the safety and efficacy of opioids.
阿片类药物是目前最有效的几种镇痛药之一。然而，其疗效受到镇痛耐受的限制。传统上，人们认为通过阿片受体（MOR）信号的脱敏和内化，会导致耐受的产生。相反的发现导致了一个最近的提议，即持续的 MOR 信号导致了镇痛耐受。然而，这种观点也受到了质疑。我们最近发现，血小板衍生生长因子受体（PDGFR）信号系统对于导致阿片类药物耐受是必需且充分的。因此，我们提出了一个全新的假说：阿片类药物耐受是由选择性细胞信号介导的，与 MOR 内化无关。为了验证这一假说，我们开发了一种基于软件的自动方法，用于对大鼠胶状质中阿片类药物诱导的 MOR 内化进行无偏分析。我们用吗啡或芬太尼诱导耐受，吗啡不会引起 MOR 内化，而芬太尼会引起 MOR 内化。我们还通过给予吗啡或芬太尼与 PDGFR 抑制剂伊马替尼来阻断耐受。我们发现，伊马替尼阻断了耐受，而没有改变吗啡或芬太尼诱导的受体内化。我们还表明，伊马替尼阻断了其他临床使用的阿片类药物的耐受。我们的研究结果表明，阿片类药物耐受不依赖于 MOR 内化，并支持了一种新的假说，即阿片类药物耐受是由可以选择性靶向的细胞内信号介导的。这表明，令人兴奋的可能性是，可以选择性地消除阿片类药物的不良副作用，从而显著提高阿片类药物的安全性和疗效。
经典上，人们认为阿片类药物的镇痛耐受是由 - 阿片受体（MOR）的脱敏和内化引起的。最近，有人提出，持续的而不是减少的 MOR 信号导致了耐受。在这里，我们提供了确凿的证据表明，阿片类药物耐受的发生与 MOR 内化无关，而是由血小板衍生生长因子受体信号选择性介导的。这个新的假说表明，危险的阿片类药物副作用可以被选择性地靶向和阻断，从而提高阿片类药物的安全性和疗效。
