Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; University of Toronto Centre for the Study of Pain, Toronto, ON, Canada.
CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec, QC, Canada.
Cell Rep. 2019 Jul 16;28(3):590-596.e4. doi: 10.1016/j.celrep.2019.06.059.
The behavioral features of neuropathic pain are not sexually dimorphic despite sex differences in the underlying neuroimmune signaling. This raises questions about whether neural processing is comparably altered. Here, we test whether the K-Cl co-transporter KCC2, which regulates synaptic inhibition, plays an equally important role in development of neuropathic pain in male and female rodents. Past studies on KCC2 tested only males. We find that inhibiting KCC2 in uninjured animals reproduces behavioral and electrophysiological features of neuropathic pain in both sexes and, consistent with equivalent injury-induced downregulation of KCC2, that counteracting chloride dysregulation reverses injury-induced behavioral and electrophysiological changes in both sexes. These findings demonstrate that KCC2 downregulation contributes equally to pain hypersensitivity in males and females. Whereas diverse (and sexually dimorphic) mechanisms regulate KCC2, regulation of intracellular chloride relies almost exclusively on KCC2. Directly targeting KCC2 thus remains a promising strategy for treatment of neuropathic pain in both sexes.
尽管神经免疫信号存在性别差异，但神经病理性疼痛的行为特征并无性别二态性。这引发了一个问题，即神经处理是否同样发生了改变。在这里，我们测试了 K-Cl 共转运蛋白 KCC2 是否在雄性和雌性啮齿动物神经病理性疼痛的发展中同样起着重要作用，KCC2 调节突触抑制。过去关于 KCC2 的研究仅测试了雄性。我们发现，在未受伤的动物中抑制 KCC2 会在两性中重现神经病理性疼痛的行为和电生理特征，并且与损伤诱导的 KCC2 下调相当，对抗氯离子失调会逆转两性中损伤诱导的行为和电生理变化。这些发现表明，KCC2 下调同样导致雄性和雌性的疼痛敏感性增加。虽然存在多种（性别二态性）调节 KCC2 的机制，但细胞内氯离子的调节几乎完全依赖于 KCC2。因此，直接针对 KCC2 仍然是治疗两性神经病理性疼痛的有前途的策略。
