Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
Pain. 2012 Apr;153(4):900-914. doi: 10.1016/j.pain.2012.01.019. Epub 2012 Feb 28.
Inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive (damage-sensing) dorsal root ganglion (DRG) neurons innervating inflamed tissue. However, most of the evidence for this is derived from experiments using acute inflammatory states. Herein, we used several approaches to examine the impact of chronic or persistent inflammation on the excitability of nociceptive DRG neurons and on their expression of I(h) and the underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which regulate neuronal excitability. Using in vivo intracellular recordings of somatic action potentials from L4/L5 DRG neurons in normal rats and rats with hindlimb inflammation induced by complete Freund's adjuvant (CFA), we demonstrate increased excitability of C- but not Aδ-nociceptors, 5 to 7 days after CFA. This included an afterdischarge response to noxious pinch, which may contribute to inflammatory mechanohyperalgesia, and increased incidence of spontaneous activity (SA) and decreased electrical thresholds, which are likely to contribute to spontaneous pain and nociceptor sensitization, respectively. We also show, using voltage clamp in vivo, immunohistochemistry and behavioral assays that (1) the inflammation-induced nociceptor hyperexcitability is associated, in C- but not Aδ-nociceptors, with increases in the mean I(h) amplitude/density and in the proportion of I(h) expressing neurons, (2) increased proportion of small DRG neurons (mainly IB4-negative) expressing HCN2 but not HCN1 or HCN3 channel protein, (3) increased HCN2- immunoreactivity in the spinal dorsal horn, and (4) attenuation of inflammatory mechanoallodynia with the selective I(h) antagonist, ZD7288. Taken together, the findings suggest that C- but not Aδ-nociceptors sustain chronic inflammatory pain and that I(h)/HCN2 channels contribute to inflammation-induced C-nociceptor hyperexcitability.
炎症性疼痛过敏部分源于伤害感受性（损伤感应）背根神经节（DRG）神经元的过度兴奋，这些神经元支配炎症组织。然而，这方面的大多数证据都来自于使用急性炎症状态的实验。在此，我们使用了几种方法来研究慢性或持续性炎症对伤害感受性 DRG 神经元兴奋性及其 Ih 的表达和潜在的超极化激活环核苷酸门控（HCN）通道的影响，这些通道调节神经元兴奋性。我们使用正常大鼠和完全弗氏佐剂（CFA）诱导后肢炎症大鼠 L4/L5 DRG 神经元体内细胞内记录的躯体动作电位，证明 C 而非 Aδ 伤害感受器的兴奋性增加，CFA 后 5 至 7 天。这包括对有害捏合的后放电反应，这可能有助于炎症性机械性痛觉过敏，以及自发性活动（SA）的发生率增加和电阈值降低，这分别可能有助于自发性疼痛和伤害感受器敏化。我们还通过体内电压钳、免疫组织化学和行为测定表明，（1）炎症诱导的伤害感受器过度兴奋与 C 而非 Aδ 伤害感受器中的 Ih 幅度/密度增加和表达 Ih 的神经元比例增加有关，（2）表达 HCN2 但不表达 HCN1 或 HCN3 通道蛋白的小 DRG 神经元（主要为 IB4 阴性）比例增加，（3）脊髓背角 HCN2 免疫反应增加，（4）选择性 Ih 拮抗剂 ZD7288 减轻炎症性机械性痛觉过敏。总之，这些发现表明 C 而非 Aδ 伤害感受器持续慢性炎症性疼痛，并且 Ih/HCN2 通道有助于炎症诱导的 C 伤害感受器过度兴奋。
