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Exploring Morphine-Triggered PKC-Targets and Their Interaction with Signaling Pathways Leading to Pain via TrkA

机译：探索吗啡触发的PKC目标及其与通过TrkA导致疼痛的信号通路的相互作用

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摘要

It is well accepted that treatment of chronic pain with morphine leads to μ opioid receptor (MOR) desensitization and the development of morphine tolerance. MOR activation by the selective peptide agonist, D-Ala2, N-MePhe4, Gly-ol]-enkephalin(DAMGO), leads to robust G protein receptor kinase activation, β-arrestin recruitment, and subsequent receptor endocytosis, which does not occur in an activation by morphine. However, MOR activation by morphine induces receptor desensitization, in a Protein kinase C (PKC) dependent manner. PKC inhibitors have been reported to decrease receptor desensitization, reduce opiate tolerance, and increase analgesia. However, the exact role of PKC in these processes is not clearly delineated. The difficulties in establishing a particular role for PKC have been, in part, due to the lack of reagents that allow the selective identification of PKC targets. Recently, we generated a conformation state-specific anti-PKC antibody that preferentially recognizes the active state of this kinase. Using this antibody to selectively isolate PKC substrates and a proteomics strategy to establish the identity of the proteins, we examined the effect of morphine treatment on the PKC targets. We found an enhanced interaction of a number of proteins with active PKC, in the presence of morphine. In this article, we discuss the role of these proteins in PKC-mediated MOR desensitization and analgesia. In addition, we posit a role for some of these proteins in mediating pain by TrKA activation, via the activation of transient receptor potential cation channel subfamily V member 1 (TRPV1). Finally, we discuss how these new PKC interacting proteins and pathways could be targeted for the treatment of pain.
机译：吗啡对慢性疼痛的治疗会导致μ阿片受体（MOR）脱敏和吗啡耐受性的发展，这是公认的。 MOR通过选择性肽激动剂D-Ala2，N-MePhe4，Gly-ol]-脑啡肽（DAMGO）激活，导致强大的G蛋白受体激酶激活，β-arrestin募集和随后的受体内吞作用，这在吗啡激活。但是，吗啡激活吗啡以蛋白激酶C（PKC）依赖的方式诱导受体脱敏。据报道，PKC抑制剂可降低受体脱敏，降低鸦片耐受性并增加镇痛作用。但是，尚未明确描述PKC在这些过程中的确切作用。建立PKC特定角色的困难部分是由于缺少允许选择性鉴定PKC靶标的试剂。最近，我们生成了一种构象状态特异性抗PKC抗体，该抗体优先识别该激酶的活性状态。使用该抗体选择性分离PKC底物和蛋白质组学策略来建立蛋白质的身份，我们检查了吗啡处理对PKC靶的影响。我们发现在吗啡存在下许多蛋白质与活性PKC的相互作用增强。在本文中，我们讨论了这些蛋白在PKC介导的MOR脱敏和镇痛中的作用。此外，我们通过介导瞬时受体电位阳离子通道亚家族V成员1（TRPV1）激活TrKA激活来介导疼痛中的某些蛋白质。最后，我们讨论了如何将这些新的PKC相互作用蛋白和途径靶向治疗疼痛。

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