Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Mol Pain. 2020 Jan-Dec;16:1744806920943334. doi: 10.1177/1744806920943334.
The neurohypophysial hormone oxytocin (OXT) is synthesized in the hypothalamic paraventricular and supraoptic nuclei. Recently, some studies have considered OXT to be important in sensory modulation and that the OXT protein is upregulated by acute and chronic nociception. However, the mechanism by which OXT is upregulated in neurons is unknown. In this study, we examined the resting membrane potentials and excitatory postsynaptic currents in OXT-ergic neurons in the paraventricular nucleus in adjuvant arthritis rat model, a model of chronic inflammation, using whole-cell patch-clamping. Transgenic rats expressing OXT and monomeric red fluorescent protein 1 (mRFP1) fusion protein to visualize the OXT-ergic neurons were used, and the OXT-mRFP1 transgenic rat model of adjuvant arthritis was developed by injection of heat-killed . Furthermore, the feedback system of synthesized OXT was also examined using the OXT receptor antagonist L-368,899. We found that the resting membrane potentials and frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-monomeric red fluorescent protein 1 neurons in the paraventricular nucleus were significantly increased in adjuvant arthritis rats. Furthermore, L-368,899 dose-dependently increased the frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-ergic neurons. Following bath application of the GABA receptor antagonist picrotoxin and the cannabinoid receptor 1 antagonist AM 251, L-368,899 still increased the frequency of miniature excitatory postsynaptic currents. However, following bath application of the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride, L-368,899 did not alter the miniature excitatory postsynaptic current frequency. Thus, it is suggested that OXT-ergic neuron activity is upregulated via an increase in glutamate release, and that the upregulated OXT neurons have a feedback system with released endogenous OXT. It is possible that nitric oxide, but not GABA, may contribute to the feedback system of OXT neurons in chronic inflammation.
神经垂体激素催产素（OXT）在下丘脑室旁核和视上核中合成。最近，一些研究认为 OXT 在感觉调制中很重要，并且 OXT 蛋白在急性和慢性痛觉传入中上调。然而，OXT 在神经元中上调的机制尚不清楚。在这项研究中，我们使用全细胞膜片钳技术，在佐剂性关节炎大鼠模型（一种慢性炎症模型）中检查了室旁核中 OXT 能神经元的静息膜电位和兴奋性突触后电流。使用表达 OXT 和单体红色荧光蛋白 1（mRFP1）融合蛋白以可视化 OXT 能神经元的转基因大鼠，并通过注射热灭活的制备 OXT-mRFP1 转基因佐剂性关节炎大鼠模型。此外，还使用 OXT 受体拮抗剂 L-368,899 检查了合成 OXT 的反馈系统。我们发现，佐剂性关节炎大鼠室旁核中 OXT-monomer 红色荧光蛋白 1 神经元的静息膜电位和微小兴奋性突触后电流及自发性兴奋性突触后电流的频率明显增加。此外，L-368,899 剂量依赖性地增加了 OXT 能神经元微小兴奋性突触后电流和自发性兴奋性突触后电流的频率。在应用 GABA 受体拮抗剂荷包牡丹碱和大麻素受体 1 拮抗剂 AM 251 后，L-368,899 仍增加微小兴奋性突触后电流的频率。然而，在应用一氧化氮合酶抑制剂 Nω-硝基-L-精氨酸甲酯盐酸盐后，L-368,899 并未改变微小兴奋性突触后电流的频率。因此，OXT 能神经元的活动通过谷氨酸释放的增加而上调，而上调的 OXT 神经元具有释放内源性 OXT 的反馈系统。一氧化氮（而不是 GABA）可能有助于慢性炎症中 OXT 神经元的反馈系统。
