Wolfson Centre for Age-Related Diseases, The Wolfson Wing, King's College London, Guy's Campus, London, United Kingdom.
PLoS One. 2013;8(1):e53673. doi: 10.1371/journal.pone.0053673. Epub 2013 Jan 16.
EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies.
EphB 受体酪氨酸激酶和 EphrinB 配体最初被鉴定为参与神经系统发育过程中拓扑映射和连接建立的导向分子。后来，在发育和成年期，它们的主要作用将从导向转变为对突触效能的活性依赖性调节。在感觉系统中，它们在炎症性和神经性疼痛的发作以及中枢敏化的建立中发挥作用，中枢敏化是一种 NMDA 介导的突触可塑性形式，被认为是大多数慢性疼痛的基础。我们在一系列炎症性和神经性疼痛模型中研究了野生型和 EphB1 敲除小鼠，以确定 1）EphB1 表达是否对于持续性疼痛的发作和/或维持是必要的，无论其来源如何；2）在这些模型中，与疼痛发作相关的细胞和分子变化，例如 NMDA 受体 NR2B 亚基的磷酸化、c-fos 表达或小胶质细胞激活，是否受到功能性 EphB1 受体缺失的影响。表型差异在行为、解剖、生化和电生理学方面进行了检查。我们的结果首先确立了功能性 EphB1 受体对于正常痛觉、热觉或机械敏感性的发展不是必需的。其次，它们证明 EphB1 受体广泛参与慢性疼痛。EphB1 敲除小鼠中 NR2B 磷酸化、c-fos 表达和小胶质细胞激活均减少。这最后一个发现很有趣，因为小胶质细胞激活据称是由初级传入纤维直接触发的，因此预计不会受到影响。有趣的是，在一些长期疼痛（数天）模型中，野生型和 EphB1 敲除小鼠均出现机械和热痛觉过敏，但后者恢复更快，表明在特定模型中，这些受体对于热和机械敏感性的维持而不是发作是必需的。这使得它们成为有吸引力的镇痛策略靶点。
