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

Acta Pharmacologica Sinica (2024)Cite this article

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 (0.28 nmol) 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 (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) 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.

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Fig. 1: MnPO neurons were innervated by LPBN neurons and activated by LPBN PGE2 injection.
Fig. 2: Effects of MnPO lesions on the febrile response triggered by intra-LPBN PGE2 injection.
Fig. 3: Effects of the selective lesioning of the LPBN-MnPO pathway on the fever response triggered by intra-LPBN PGE2 injection.
Fig. 4: Effects of the chemogenetic inhibition of the LPBN-MnPO pathway on fever induced by intra-LPBN PGE2.
Fig. 5: Effects of the microinjection of EP3, EP4, or EP1 agonists and antagonists into the LPBN on Tcore and EE in conscious rats.
Fig. 6: Effects of LPBN PGE2 administration on Trec, BAT SNA, TBAT, Ttail, and EMG activities were abolished by pretreatment with the EP3 antagonist and mimicked by the EP3 agonist in anesthetized rats.
Fig. 7: Actions of PGE2, EP3 agonist, and EP3 antagonist on the firing rate of MnPO-projecting LPBN neurons.
Fig. 8: Effects of PGE2, EP3 agonist, and EP3 antagonist on excitatory and inhibitory synaptic transmission of MnPO-projecting LPBN neurons.
Fig. 9: Effects of PGE2, EP3 agonist, and EP3 antagonist on IA currents in MnPO-projecting LPBN neurons.
Fig. 10: Schematic of the proposed neural mechanism of the pyrogenic response to PGE2 synthesized in LPBN during LPS-induced fever.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (32100926 (JHX) and 31771289 (JZ)), Disciplinary Contraction Innovation Team Foundation (CMC-XK-21XX) and Graduates Innovating Experimentation Project (YCX2022-01, THH) of Chengdu Medical College. The authors thank Dr Wei L. Shen (School of Life Science and Technology, ShanghaiTech University) for his suggestions and technical support.

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  1. These authors contributed equally: Jian-hui Xu, Tian-hui He

Authors and Affiliations

  1. Key Laboratory of Thermoregulation and Inflammation of Sichuan Higher Education Institutes, Chengdu Medical College, Chengdu, 610500, China

    Jian-hui Xu, Tian-hui He, Nan-ping Wang, Wen-min Gao, Yong-jing Cheng, Qiao-feng Ji, Yu Tang & Jie Zhang

  2. School of Clinical Medicine, Chengdu Medical College, Chengdu, 610500, China

    Si-hao Wu & Yan-lin Wei

  3. School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China

    Wen Z. Yang

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Contributions

JHX and THH designed and conducted the experiments, analyzed and interpreted the data. NPW, WMG, YJC, QFJ, SHW, and YLW performed the experiments. YT analyzed the data. WZY designed the experiments and revised the manuscript. JZ designed, coordinated, and performed the experiments, and wrote the manuscript. All authors read and approved the article.

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Xu, Jh., He, Th., Wang, Np. et al. Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01289-6

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