Nutrition Research Unit, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Neuroscience. 2018 Aug 10;385:102-120. doi: 10.1016/j.neuroscience.2018.06.013. Epub 2018 Jun 15.
Neonatal injury-induced exaggeration of pain hypersensitivity after adult trauma is a significant clinical challenge. However, the underlying mechanisms remain poorly understood. Growing evidence shows that spinal Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) contributes to chronic pain in adult rodents. Here we demonstrated that the phosphorylation and expression of SHP2 in synaptosomal fraction of the spinal dorsal horn are elevated in adult rats subjected to neonatal and adult incisions (nIN-IN), and the upregulation of SHP2 is highly correlated with pain hypersensitivity. Intrathecal blockade of SHP2 phosphorylation using a SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of SHP2 by intrathecal delivery of small interfering RNA (siRNA), ameliorates mechanical allodynia and heat hyperalgesia in nIN-IN rats. Moreover, the expression of phosphatidylinositol 3-kinase (PI3K) in the spinal dorsal horn is significantly increased in nIN-IN rats. Intrathecal application of PI3K inhibitor, LY294002 or wortmannin, alleviates pain hypersensitivity in nIN-IN rats. Additionally, intrathecal administration of NSC-87877 or SHP2 siRNA attenuates the upregulation of PI3K. Finally, no alternation of SHP2 phosphorylation in the dorsal root ganglion and dorsal root of nIN-IN rats as well as PI3K expression in the dorsal root of nIN-IN rats intrathecally treated with NSC-87877 or SHP2 siRNA is observed. These results suggest that the phosphorylation and expression of SHP2 in the spinal dorsal horn play vital roles in neonatal incision-induced exaggeration of adult incisional pain via PI3K. Thus, SHP2 and PI3K may serve as potential therapeutic targets for exaggerated incisional pain induced by neonatal and adult injuries.
新生儿损伤引起的成年创伤后疼痛敏感性过度增强是一个重大的临床挑战。然而，其潜在机制仍知之甚少。越来越多的证据表明，脊髓Src 同源性-2 结构域含有蛋白酪氨酸磷酸酶-2（SHP2）有助于成年啮齿动物的慢性疼痛。在这里，我们证明了在接受新生儿和成年切口（nIN-IN）的成年大鼠的脊髓背角突触小体部分中，SHP2 的磷酸化和表达增加，并且 SHP2 的上调与疼痛敏感性过度增强高度相关。使用 SHP2 蛋白酪氨酸磷酸酶抑制剂 NSC-87877 或鞘内递送小干扰 RNA（siRNA）抑制 SHP2 的磷酸化，可改善 nIN-IN 大鼠的机械性痛觉过敏和热痛觉过敏。此外，nIN-IN 大鼠脊髓背角中的磷脂酰肌醇 3-激酶（PI3K）表达显著增加。鞘内应用 PI3K 抑制剂 LY294002 或wortmannin 可减轻 nIN-IN 大鼠的痛觉过敏。此外，鞘内给予 NSC-87877 或 SHP2 siRNA 可减轻 PI3K 的上调。最后，在鞘内给予 NSC-87877 或 SHP2 siRNA 的 nIN-IN 大鼠的背根神经节和背根中未观察到 SHP2 磷酸化的改变以及 nIN-IN 大鼠背根中的 PI3K 表达。这些结果表明，脊髓背角中 SHP2 的磷酸化和表达通过 PI3K 在新生儿切口引起的成年切口痛觉过敏过度增强中起关键作用。因此，SHP2 和 PI3K 可能是新生儿和成年损伤引起的切口痛觉过敏过度的潜在治疗靶点。
