Indirect AMP-Activated Protein Kinase Activators Prevent Incision-Induced Hyperalgesia and Block Hyperalgesic Priming, Whereas Positive Allosteric Modulators Block Only Priming in Mice
Indirect AMP-Activated Protein Kinase Activators Prevent Incision-Induced Hyperalgesia and Block Hyperalgesic Priming, Whereas Positive Allosteric Modulators Block Only Priming in Mice
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DOI：
10.1124/jpet.119.258400
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发表时间：
2019-10-01
影响因子：
3.5
通讯作者：
Price, Theodore J.
中科院分区：
文献类型：
--
作者：
Inyang, Kufreobong E.;Burton, Michael D.;Price, Theodore J.
amp活化蛋白激酶（AMPK）是一种负调控雷帕霉素（mTOR）和丝裂原活化蛋白激酶（MAPK）信号传导的机制靶点的多功能激酶，这两种信号通路与手术切口等损伤后疼痛促进有关。AMPK可以通过正变构调节剂直接激活，也可以通过上调上游激酶如肝激酶B1 （LKB1）间接激活，这是二甲双胍的作用机制之一。二甲双胍的抗痛觉作用只发生在雄性小鼠身上，这就提出了二甲双胍如何调节疼痛敏感性的问题。我们使用二甲双胍和其他结构不同的AMPK激活剂水仙素（NCLS）、ZLN-024和MK8722来治疗雄性和雌性小鼠切口诱导的机械超敏反应和痛感引发。二甲双胍是唯一具有性别特异性效应的AMPK激活剂。我们还发现，间接AMPK激活剂二甲双胍和NCLS能够减少机械超敏反应并阻断痛感引发，而直接AMPK激活剂ZLN-024和MK8722只能阻断引发。直接和间接AMPK激活剂对背根神经节（DRG）神经元培养中AMPK的刺激程度相似；然而，切口降低了DRG中磷酸化的AMPK （p-AMPK）。由于AMPK磷酸化是激酶活性所必需的，我们将我们的研究结果解释为间接AMPK激活剂对治疗切口后疼痛超敏反应更有效的证据，因为它们可以通过上游激酶如LKB1驱动p-AMPK的增加。这些发现对开发以ampk为靶点的疼痛治疗药物具有重要意义。意义：术后疼痛需要非阿片类药物治疗。我们的工作重点是直接或间接的amp激活蛋白激酶（AM PK）激活剂是否对抑制切口疼痛更有效，我们也测试了潜在的性别差异。我们得出的结论是，间接AMPK激活剂可能更有效地治疗术后疼痛，因为它们抑制了切口引起的急性疼痛，并阻止了长期的神经元可塑性，这涉及到持续的术后疼痛。我们的工作指出，天然产物水仙素是一种间接的AMPK激活剂，是开发治疗方法的一个很好的起点。
AMP-activated protein kinase (AMPK) is a multifunctional kinase that negatively regulates the mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling, two signaling pathways linked to pain promotion after injury, such as surgical incision. AMPK can be activated directly using positive allosteric modulators, as well as indirectly through the upregulation of upstream kinases, such as liver kinase B1 (LKB1), which is a mechanism of action of metformin. Mefformin's antihyperalgesic effects occur only in male mice, raising questions about how metformin regulates pain sensitivity. We used metformin and other structurally distinct AMPK activators narciclasine (NCLS), ZLN-024, and MK8722, to treat incision-induced mechanical hypersensitivity and hyperalgesic priming in male and female mice. Metformin was the only AMPK activator to have sex-specific effects. We also found that indirect AMPK activators metformin and NCLS were able to reduce mechanical hypersensitivity and block hyperalgesic priming, whereas direct AMPK activators ZLN-024 and MK8722 only blocked priming. Direct and indirect AMPK activators stimulated AMPK in dorsal root ganglion (DRG) neuron cultures to a similar degree; however, incision decreased phosphorylated AMPK (p-AMPK) in DRG. Because AMPK phosphorylation is required for kinase activity, we interpret our findings as evidence that indirect AMPK activators are more effective for treating pain hypersensitivity after incision because they can drive increased p-AMPK through upstream kinases like LKB1. These findings have important implications for the development of AMPK-targeting therapeutics for pain treatment.SIGNIFICANCE STATEMENT Nonopioid treatments for postsurgical pain are needed. Our work focused on whether direct or indirect AMP-activated protein kinase (AM PK) activators would show greater efficacy for inhibiting incisional pain, and we also tested for potential sex differences. We conclude that indirect AMPK activators are likely to be more effective as potential therapeutics for postsurgical pain because they inhibit acute pain caused by incision and prevent the long-term neuronal plasticity that is involved in persistent postsurgical pain. Our work points to the natural product narciclasine, an indirect AMPK activator, as an excellent starting point for development of therapeutics.