Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females
Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females
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DOI：
10.1097/j.pain.0000000000001470
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发表时间：
2019-04-01
期刊：
影响因子：
7.4
通讯作者：
Bethea, John R.
中科院分区：
文献类型：
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作者：
del Rivero, Tania;Fischer, Roman;Bethea, John R.
肿瘤坏死因子（tumor necrosis factor，TNF）是一种促炎性细胞因子，参与多种生理和病理过程，在疼痛的发生发展中起着重要作用。在本研究中，我们感兴趣的是阻断肿瘤坏死因子受体1（TNFR 1）信号转导对周围神经损伤后神经病理性疼痛的影响，使用转基因小鼠和药理学抑制。我们先前已经表明TNFR 12/2小鼠在慢性压迫性损伤（CCI）后没有发展神经性疼痛和抑郁症状。为了研究损伤后抑制TNFR 1信号传导的治疗效果，我们递送了一种使可溶性TNF（XPro 1595）失活的药物。抑制solTNF信号导致加速恢复神经性疼痛的男性，但不是在女性。为了开始探索一种机制，我们研究了N-甲基-D-天冬氨酸（NMDA）受体的变化，因为神经性疼痛已被证明会引起神经递质信号的增加。在雄性小鼠中，XPro 1595治疗降低了损伤后大脑中升高的NMDA受体水平，而在雌性小鼠中，CCI后NMDA受体水平降低。我们进一步表明，雌激素抑制XPro 1595在女性中的治疗反应。我们的研究结果表明，TNFR 1信号在CCI后的疼痛诱导中起着至关重要的作用，但在女性中则不然。
Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is involved in physiological and pathological processes and has been found to be crucial for pain development. In the current study, we were interested in the effects of blocking Tumor necrosis factor receptor 1 (TNFR1) signaling on neuropathic pain after peripheral nerve injury with the use of transgenic mice and pharmacological inhibition. We have previously shown that TNFR12/2 mice failed to develop neuropathic pain and depressive symptoms after chronic constriction injury (CCI). To investigate the therapeutic effects of inhibiting TNFR1 signaling after injury, we delivered a drug that inactivates soluble TNF (XPro1595). Inhibition of solTNF signaling resulted in an accelerated recovery from neuropathic pain in males, but not in females. To begin exploring a mechanism, we investigated changes in N-methyl-D-aspartate (NMDA) receptors because neuropathic pain has been shown to invoke an increase in glutamatergic signaling. In male mice, XPro1595 treatment reduces elevated NMDA receptor levels in the brain after injury, whereas in female mice, NMDA receptor levels decrease after CCI. We further show that estrogen inhibits the therapeutic response of XPro1595 in females. Our results suggest that TNFR1 signaling plays an essential role in pain induction after CCI in males but not in females.