Hypoxia-Inducible Factor 1 Regulates Heat and Cold Pain Sensitivity and Persistence
Hypoxia-Inducible Factor 1 Regulates Heat and Cold Pain Sensitivity and Persistence
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DOI：
10.1089/ars.2013.5494
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发表时间：
2014-06-01
影响因子：
6.6
通讯作者：
Tegeder, Irmgard
中科院分区：
文献类型：
--
作者：
Kanngiesser, Maike;Mair, Norbert;Tegeder, Irmgard
目的：本研究评估了缺氧诱导因子（HIF）在急性、炎症、缺血和神经病理性疼痛模型中感觉神经元中的功能。通过将HIF 1（fl/fl）小鼠与SNScre小鼠交配，在背根神经节的神经元中特异性地缺失α亚基HIF 1。结果：SNS-HIF 1（-/-）小鼠对伤害性热痛和冷痛刺激比HIF 1（fl/fl）对照小鼠更敏感。他们还表现出在福尔马林和辣椒素测试中第一阶段伤害性反应增强，背角中cFos阳性神经元的数量增加，并且在爪炎症和后肢缺血/再灌注后的早期阶段增强痛觉过敏。SNS-HIF 1（-/-）小鼠初级感觉神经元瞬时受体电位通道激活后钙流增加，感觉纤维电激活阈值降低，从而解释了行为性冷热痛超敏反应。然而，SNS-HIF 1（-/-）小鼠在坐骨神经损伤后发生较少的神经性疼痛，这与HIF 1介导的基因上调的废除有关。创新：结果表明，HIF 1在急性热和冷痛方面具有保护作用，但在受损神经元持续激活的情况下，它可能促进神经病理性疼痛的发展。结论：HIF 1在疼痛调节中的双重性可能对靶向HIF 1的药物的副作用产生影响，这些药物正在开发，例如，作为抗癌剂。具体来说，在患有癌症神经病变的患者中，暂时的HIF 1抑制可能提供生长和疼痛减轻的受欢迎组合。抗氧化剂。氧化还原信号。20，2555-2571。
Aims: The present study assessed the functions of the transcription factor hypoxia-inducible factor (HIF) in sensory neurons in models of acute, inflammatory, ischemic, and neuropathic pain. The alpha subunit, HIF1, was specifically deleted in neurons of the dorsal root ganglia by mating HIF1(fl/fl) mice with SNScre mice. Results: SNS-HIF1(-/-) mice were more sensitive to noxious heat and cold pain stimulation than were HIF1(fl/fl) control mice. They also showed heightened first-phase nociceptive responses in the formalin and capsaicin tests with increased numbers of cFos-positive neurons in the dorsal horn, and intensified hyperalgesia in early phases after paw inflammation and hind limb ischemia/reperfusion. The behavioral cold and heat pain hypersensitivity was explained by increased calcium fluxes after transient receptor potential channel activation in primary sensory neurons of SNS-HIF1(-/-) mice and lowered electrical activation thresholds of sensory fibers. SNS-HIF1(-/-) mice however, developed less neuropathic pain after sciatic nerve injury, which was associated with an abrogation of HIF1-mediated gene up-regulation. Innovation: The results suggest that HIF1 is protective in terms of acute heat and cold pain but in case of ongoing activation in injured neurons, it may promote the development of neuropathic pain. Conclusion: The duality of HIF1 in pain regulation may have an impact on the side effects of drugs targeting HIF1, which are being developed, for example, as anticancer agents. Specifically, in patients with cancer neuropathy, however, temporary HIF1 inhibition might provide a welcome combination of growth and pain reduction. Antioxid. Redox Signal. 20, 2555-2571.