Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
J Neurosci. 2021 Mar 10;41(10):2091-2105. doi: 10.1523/JNEUROSCI.2036-20.2021. Epub 2021 Jan 20.
Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain. Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.
三叉神经病理性疼痛是最使人虚弱的疼痛障碍，但目前包括阿片类药物在内的治疗方法并不有效。三叉神经病理性疼痛的常见症状是面部区域的冷感觉异常/痛觉过敏或冷过敏，在日常生活中，这些区域不可避免地会接触到降温温度。导致三叉神经病理性疼痛表现为冷过敏的机制尚不完全清楚。在这项研究中，我们通过眶下神经慢性缩窄性损伤（ION-CCI）研究了雄性大鼠的三叉神经病理性疼痛。通过口腔操作性行为测试评估，ION-CCI 动物表现出口面部冷过敏。这种冷过敏与支配面部区域的小尺寸三叉神经节（TG）神经元的过度兴奋有关。此外，ION-CCI 导致这些 TG 神经元中的 A 型电压门控 K 电流（IA 电流）减少。我们进一步表明，这些小尺寸 TG 神经元表达 Kv4.3 电压门控 K 通道，并且在 ION-CCI 后这些细胞中的 Kv4.3 表达明显下调。用 phrixotoxin-2 抑制 Kv4.3 通道可抑制这些 TG 神经元中的 IA 电流，并诱导口面部冷过敏。另一方面，药理学增强 Kv4.3 通道可放大这些 TG 神经元中的 IA 电流，并缓解 ION-CCI 大鼠的口面部冷过敏。总体而言，伤害性三叉神经传入纤维中的 Kv4.3 下调可能导致三叉神经损伤后的外周冷过敏，并且 Kv4.3 激活剂可能在临床上用于缓解三叉神经病理性疼痛。三叉神经病理性疼痛是最使人虚弱的疼痛障碍，常由降温温度引发和加重。在这里，我们在大鼠中创建了眶下神经慢性缩窄性损伤（ION-CCI），这是一种三叉神经病理性疼痛的动物模型，以表明伤害感受样三叉神经节（TG）神经元中 Kv4.3 电压门控 K 通道的功能障碍是导致面部区域冷过敏的三叉神经病理性疼痛的基础。此外，我们证明药理学增强 Kv4.3 通道可以缓解 ION-CCI 大鼠的口面部冷过敏。我们的结果可能对人类患者的三叉神经病理性疼痛具有临床意义，并且 Kv4.3 通道可能是这种破坏性疼痛障碍的有效治疗靶点。
