Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model
Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model
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白细胞介素6通过激活JAK/PI3K信号通路介导背根神经节神经元TRPV1受体的功能上调：在大鼠模型骨癌疼痛发展中的作用
DOI：
10.1097/j.pain.0000000000000158
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发表时间：
2015-06-01
期刊：
影响因子：
7.4
通讯作者：
Xing, Guo-Gang
中科院分区：
文献类型：
--
作者：
Fang, Dong;Kong, Ling-Yu;Xing, Guo-Gang
影响骨的原发性和转移性癌症通常与严重和难治性疼痛相关。骨癌疼痛的发病机制在很大程度上仍然是未知的。以前，我们已经报道了初级感觉背根神经节（DRG）神经元的致敏参与了大鼠骨癌疼痛的发病机制。此外，大量的临床前和临床研究已经揭示了白细胞介素-6 （IL-6）在炎症性和神经性痛觉过敏中的病理作用。在这项研究中，我们通过体外和体内方法研究了IL-6在骨癌疼痛发展中的作用和潜在机制。我们首先证明了DRG神经元中升高的IL-6通过IL-6/可溶性IL-6受体（sIL-6R）反式信号传导在伤害感受器致敏和骨癌诱导的大鼠疼痛模型中起重要作用。此外，我们发现通过激活Janus激酶(JAK)/磷脂酰肌醇3-激酶（PI3K）信号通路，DRG神经元中瞬时受体电位香草酸通道1 （TRPV1）的功能上调参与了IL-6在骨癌疼痛发病机制中的作用。因此，无论是术前还是术后，通过抑制JAK/PI3K通路抑制DRG神经元TRPV1的功能性上调，均可降低骨癌大鼠DRG神经元的高兴奋性和痛觉过敏。我们在这里揭示了一种新的细胞内通路，IL-6/JAK/PI3K/TRPV1信号级联，它可能是外周致敏和骨癌诱导疼痛发展的基础。
Abstract Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the pathogenesis of bone cancer pain still remain largely unknown. Previously, we have reported that sensitization of primary sensory dorsal root ganglion (DRG) neurons contributes to the pathogenesis of bone cancer pain in rats. In addition, numerous preclinical and clinical studies have revealed the pathological roles of interleukin-6 (IL-6) in inflammatory and neuropathic hyperalgesia. In this study, we investigated the role and the underlying mechanisms of IL-6 in the development of bone cancer pain using in vitro and in vivo approaches. We first demonstrated that elevated IL-6 in DRG neurons plays a vital role in the development of nociceptor sensitization and bone cancer–induced pain in a rat model through IL-6/soluble IL-6 receptor (sIL-6R) trans-signaling. Moreover, we revealed that functional upregulation of transient receptor potential vanilloid channel type 1 (TRPV1) in DRG neurons through the activation of Janus kinase (JAK)/phosphatidylinositol 3-kinase (PI3K) signaling pathway contributes to the effects of IL-6 on the pathogenesis of bone cancer pain. Therefore, suppression of functional upregulation of TRPV1 in DRG neurons by the inhibition of JAK/PI3K pathway, either before surgery or after surgery, reduces the hyperexcitability of DRG neurons and pain hyperalgesia in bone cancer rats. We here disclose a novel intracellular pathway, the IL-6/JAK/PI3K/TRPV1 signaling cascade, which may underlie the development of peripheral sensitization and bone cancer–induced pain.