成都医学院Jie Zhang等研究人员合作揭示前列腺素E₂的发热效应在雄性大鼠臂旁外侧核的热调节途径。这一研究成果于2024年5月3日在线发表在国际学术期刊《中国药理学报》上。

研究表明，臂旁外侧核（LPBN）合成的前列腺素（PG）E₂参与了脂多糖诱导的发热。但是，LPBN内PGE₂如何诱导发热的神经机制仍不清楚。

研究人员探讨了LPBN-视前区（POA）通路（前馈体温调节反应的温度传感器通路）是否介导了LPBN内PGE₂诱导雄性大鼠发热。研究人员使用植入大鼠腹部的体温遥测转发器来监测核心温度（T_core）。研究结果表明，向LPBN显微注射PGE₂（0.28 nmol）可显著提高视前区中线（MnPO）c-Fos 阳性神经元的密度。用ibotenate对MnPO进行化学损伤或选择性遗传损伤或抑制LPBN-MnPO通路可明显减轻LPBN内注射PGE₂所诱导的发热。

研究人员证明了EP3受体是PGE₂诱导发热的关键受体，因为向LPBN显微注射EP3受体激动剂 sulprostone（0.2 nmol）或EP3受体拮抗剂L-798106（2 nmol）可分别模拟或削弱LPBN PGE₂的发热效应，但EP4和EP1受体的情况并非如此。对急性LPBN切片的全细胞记录显示，PGE₂灌注可分别激发和抑制源自LPBN外侧（el）和背侧（d）的大多数MnPO投射神经元，启动热获得和热丧失机制。

灌注PGE₂后，MnPO投射的LPBel神经元的自发和微型谷氨酸能兴奋性突触后电流（sEPSC和mEPSC）的振幅增加，但频率没有增加；而自发抑制性突触后电流（sIPSC）的频率和振幅以及A型钾（I_A）电流密度没有变化。在投射MnPO的LPBd神经元中，sEPSC和sIPSC对PGE₂均无反应；但I_A电流密度在灌注PGE₂后显著增加。L-798106可取消这些电生理反应以及LPBN内注射PGE₂的发热效应，包括棕色脂肪组织产热增加、颤抖和散热减少，而硫前列酮可模拟这些反应。

这些结果表明，LPBN内PGE₂的发热效应是通过EP3受体介导的I_A电流激活抑制LPBd-POA通路和通过EP3受体选择性增强谷氨酸能突触传递激活LPBel-POA通路介导的。

附：英文原文

Title: Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats

Author: Xu, Jian-hui, He, Tian-hui, Wang, Nan-ping, Gao, Wen-min, Cheng, Yong-jing, Ji, Qiao-feng, Wu, Si-hao, Wei, Yan-lin, Tang, Yu, Yang, Wen Z., Zhang, Jie

Issue&Volume: 2024-05-03

Abstract: It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2nmol) or EP3 receptor antagonist L-798106 (2nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

DOI: 10.1038/s41401-024-01289-6

Source: https://www.nature.com/articles/s41401-024-01289-6