Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Science. 2011 Sep 9;333(6048):1462-6. doi: 10.1126/science.1206243.
The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.
伤害感受器中动作电位的发放频率是疼痛强度的主要决定因素。动作电位发放的可能调节剂包括 HCN 离子通道，该通道在膜超极化后产生内向电流 I(h)。我们发现，HCN2 的基因缺失消除了 I(h)中的环腺苷单磷酸 (cAMP)敏感成分，并消除了升高 cAMP 在伤害感受器中引起的动作电位发放。在表达 Na(V)1.8 的伤害感受器中特异性缺失 HCN2 的小鼠具有正常的痛阈，但炎症不会导致对热刺激的痛觉过敏。在神经损伤后，这些小鼠对热或机械刺激没有表现出神经性疼痛。因此，神经性疼痛是由表达 Na(V)1.8 的伤害感受器中 HCN2 驱动的动作电位发放引起的。
