Kubo Asako, Shinoda Masamichi, Katagiri Ayano, Takeda Mamoru, Suzuki Tatsuro, Asaka Junichi, Yeomans David C, Iwata Koichi
Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan.
Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
Pain. 2017 Apr;158(4):649-659. doi: 10.1097/j.pain.0000000000000808.
Oxytocin (OXT) is a neuropeptide hormone synthesized and secreted by hypothalamic neurons and has been reported to play a significant role in pain modulation. However, the mechanisms underlying OXT's antinociceptive effect on neuropathic pain are not fully understood. In this study, we examined the peripheral effect of OXT on mechanical hypersensitivity induced by partial ligation of the infraorbital nerve (PNL) in rats. Mechanical hypersensitivity in the whisker pad skin after PNL was attenuated by the direct administration of OXT into the trigeminal ganglion (TG). The proportion of vasopressin-1A receptor (V1A-R)-immunoreactive, but not OXT-receptor-immunoreactive, neurons significantly increased among TG neurons innervating the whisker pad skin after PNL. In a patch-clamp recording from TG neurons isolated from PNL rats, the resting membrane potential of OXT-treated neurons was significantly decreased, and the current thresholds of OXT-treated neurons for spike generation (rheobases) were significantly greater than those of vehicle-treated neurons. In addition, OXT increased voltage-gated K channel currents in PNL animals. Furthermore, intra-TG administration of a selective V1A-R antagonist reversed the OXT-induced alleviation of mechanical hypersensitivity, and coapplication of the antagonist opposed OXT's effects on the resting membrane potential, rheobase, and K current. These findings suggest that OXT is effective at suppressing TG neuronal hyperexcitability after nerve injury, likely by modulation of voltage-gated K channels through V1A-R. This signaling mechanism represents a potential therapeutic target for the treatment of orofacial neuropathic pain.
催产素（OXT）是一种由下丘脑神经元合成并分泌的神经肽激素，据报道在疼痛调节中发挥重要作用。然而，OXT对神经性疼痛的抗伤害感受作用的潜在机制尚未完全明确。在本研究中，我们检测了OXT对大鼠眶下神经部分结扎（PNL）诱导的机械性超敏反应的外周作用。通过将OXT直接注入三叉神经节（TG），可减轻PNL后触须垫皮肤处的机械性超敏反应。在支配PNL后触须垫皮肤的TG神经元中，血管加压素-1A受体（V1A-R）免疫反应阳性神经元的比例显著增加，而OXT受体免疫反应阳性神经元的比例未增加。在从PNL大鼠分离的TG神经元进行的膜片钳记录中，OXT处理的神经元静息膜电位显著降低，且OXT处理的神经元产生动作电位的电流阈值（强度阈值）显著高于溶剂处理的神经元。此外，OXT增加了PNL动物的电压门控钾通道电流。此外，向TG内注射选择性V1A-R拮抗剂可逆转OXT诱导的机械性超敏反应的减轻，且该拮抗剂的共同应用可对抗OXT对静息膜电位、强度阈值和钾电流的作用。这些发现表明，OXT可能通过V1A-R调节电压门控钾通道，有效抑制神经损伤后TG神经元的过度兴奋。这种信号传导机制代表了治疗口面部神经性疼痛的潜在治疗靶点。
