Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice. In addition, we found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. We propose that the increased intracellular cAMP drives diabetes-associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers. Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.

糖尿病患者经常遭受持续性疼痛，目前可用的镇痛剂治疗效果不佳。我们使用 1 型和 2 型糖尿病的小鼠模型来研究超极化激活的环核苷酸门控 2 (HCN2) 离子通道作为糖尿病疼痛驱动因素的可能作用。阻断或基因删除小型伤害性神经元中的 HCN2 通道可抑制糖尿病相关的机械性异常性疼痛，并阻止小鼠脊髓中二级神经元的神经元激活。此外，我们发现在疼痛性糖尿病动物模型中，细胞内环磷酸腺苷 (cAMP) 是一种正 HCN2 调节剂，它在体感神经元中增加。我们提出增加的细胞内 cAMP 通过促进 HCN2 激活并因此促进初级伤害性神经纤维的重复放电来驱动糖尿病相关的疼痛。我们的研究结果表明，HCN2 可能是治疗疼痛性糖尿病神经病变的镇痛靶点。