Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Acta Pharmacologica Sinica volume 45, pages 1832–1847 (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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Blomqvist A, Engblom D. Neural mechanisms of inflammation-induced fever. Neuroscientist. 2018;24:381–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 2015;15:335–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Machado NLS, Bandaru SS, Abbott SBG, Saper CB. EP3R-expressing glutamatergic preoptic neurons mediate inflammatory fever. J Neurosci. 2020;40:2573–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Song K, Wang H, Kamm GB, Pohle J, Reis FC, Heppenstall P, et al. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science. 2016;353:1393–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Nakamura K, Morrison SF. A thermosensory pathway that controls body temperature. Nat Neurosci. 2008;11:62–71.

    Article  PubMed  CAS  Google Scholar 

  6. Nakamura K, Morrison SF. A thermosensory pathway mediating heat-defense responses. Proc Natl Acad Sci USA. 2010;107:8848–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Nakamura K, Nakamura Y, Kataoka N. A hypothalamomedullary network for physiological responses to environmental stresses. Nat Rev Neurosci. 2022;23:35–52.

    Article  PubMed  CAS  Google Scholar 

  8. Geerling JC, Kim M, Mahoney CE, Abbott SB, Agostinelli LJ, Garfield AS, et al. Genetic identity of thermosensory relay neurons in the lateral parabrachial nucleus. Am J Physiol Regul Integr Comp Physiol. 2016;310:R41–54.

    Article  PubMed  Google Scholar 

  9. Engblom D, Ek M, Ericsson-Dahlstrand A, Blomqvist A. Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide. J Comp Neurol. 2001;440:378–86.

    Article  PubMed  CAS  Google Scholar 

  10. Buller KM, Allen T, Wilson LD, Munro F, Day TA. A critical role for the parabrachial nucleus in generating central nervous system responses elicited by a systemic immune challenge. J Neuroimmunol. 2004;152:20–32.

    Article  PubMed  CAS  Google Scholar 

  11. Skibicka KP, Alhadeff AL, Leichner TM, Grill HJ. Neural controls of prostaglandin 2 pyrogenic, tachycardic, and anorexic actions are anatomically distributed. Endocrinology. 2011;152:2400–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Cheng YJ, Xu JH, Zeng RX, Zhao X, Gao WM, Quan JR, et al. The role of prostaglandin E2 synthesized in rat lateral parabrachial nucleus in LPS-iduced fever. Neuroendocrinology. 2022;112:399–416.

    Article  PubMed  CAS  Google Scholar 

  13. Tkacs NC, Li J. Immune stimulation induces Fos expression in brainstem amygdala afferents. Brain Res Bull. 1999;48:223–31.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang YH, Lu J, Elmquist JK, Saper CB. Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain. J Comp Neurol. 2003;463:3–12.

    Article  PubMed  CAS  Google Scholar 

  15. Jagot F, Gaston-Breton R, Choi AJ, Pascal M, Lena Bourhy L, Dorado-Doncel R, et al. The parabrachial nucleus elicits a vigorous corticosterone feedback response to the pro-inflammatory cytokine IL-1β. Neuron. 2023;111:2367–82.

    Article  PubMed  CAS  Google Scholar 

  16. Kohler C, Schwarcz R. Comparison of ibotenate and kainate neurotoxicity in rat brain: a histological study. Neuroscience. 1983;8:819–35.

    Article  PubMed  CAS  Google Scholar 

  17. Mu D, Deng J, Liu KF, Wu ZY, Shi YF, Guo WM, et al. A central neural circuit for itch sensation. Science. 2017;357:695–9.

    Article  PubMed  CAS  Google Scholar 

  18. Xue YW, Yang YL, Tang Y, Ye MP, Xu JH, Zeng YZ, et al. In vitro thermosensitivity of rat lateral parabrachial neurons. Neurosci Lett. 2016;619:15–20.

    Article  PubMed  CAS  Google Scholar 

  19. Xu JH, Tang Y, Qi HP, Yu XY, Liu MX, Wang N, et al. Electrophysiological properties of thermosensitive neurons in slices of rat lateral parabrachial nucleus. J Therm Biol. 2019;83:87–94.

    Article  PubMed  Google Scholar 

  20. Ren S, Wang Y, Yue F, Cheng X, Dang R, Qiao Q, et al. The paraventricular thalamus is a critical thalamic area for wakefulness. Science. 2018;362:429–34.

    Article  PubMed  CAS  Google Scholar 

  21. Li XY, Han Y, Zhang W, Wang SR, Wei YC, Li SS, et al. AGRP neurons project to the medial preoptic area and modulate maternal nest-building. J Neurosci. 2019;39:456–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhao Y, Boulant JA. Temperature effects on neuronal membrane potentials and inward currents in rat hypothalamic tissue slices. J Physiol. 2005;564:245–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Wrobel LJ, Reymond-Marron I, Dupré A, Raggenbass M. Oxytocin  and vasopressin enhance synaptic transmission in the hypoglossal motor nucleus of young rats by acting on distinct receptor types. Neuroscience. 2010;165:723–35.

    Article  PubMed  CAS  Google Scholar 

  24. Xu JH, Gao WM, He TH, Yao L, Wu HH, Chen ZW, et al. The hyperthermic response to intra-preoptic area administration of agmatine in male rats. J Therm Biol. 2023;113:103529.

    Article  PubMed  CAS  Google Scholar 

  25. Kataoka N, Shima Y, Nakajima K, Nakamura K. A central master driver of psychosocial stress responses in the rat. Science. 2020;367:1105–12.

    Article  PubMed  CAS  Google Scholar 

  26. Zhang J, Rivest S. Distribution, regulation and colocalization of the genes encoding the EP2- and EP4-PGE2 receptors in the rat brain and neuronal responses to systemic inflammation. Eur J Neurosci. 1999;11:2651–68.

    Article  PubMed  CAS  Google Scholar 

  27. Simm B, Ott D, Pollatzek E, Murgott J, Gerstberger R, Rummel C, et al. Effects of prostaglandin E2 on cells cultured from the rat organum vasculosum laminae terminalis and median preoptic nucleus. Neuroscience. 2016;313:23–35.

    Article  PubMed  CAS  Google Scholar 

  28. Chen C, Bazan NG. Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2005;93:929–41.

    Article  PubMed  CAS  Google Scholar 

  29. Mizutani Y, Ohi Y, Kimura S, Miyazawa K, Goto S, Haji A. Effects of prostaglandin E2 on synaptic transmission in the rat spinal trigeminal subnucleus caudalis. Brain Res. 2015;1625:29–38.

    Article  PubMed  CAS  Google Scholar 

  30. Li GY, Wu QZ, Song TJ, Zhen XC, Yu X. Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain. Acta Pharmacol Sin. 2023;44:1109–21.

    Article  PubMed  CAS  Google Scholar 

  31. Redman S. Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol Rev. 1990;70:165–98.

    Article  PubMed  CAS  Google Scholar 

  32. Hayward LF, Felder RB. Electrophysiological properties of rat lateral parabrachial neurons in vitro. Am J Physiol. 1999;276:R696–706.

    PubMed  CAS  Google Scholar 

  33. Siwiec M, Kusek M, Sowa JE, Tokarski K, Hess G. 5-HT7 receptors increase the excitability of hippocampal CA1 pyramidal neurons by inhibiting the A-type potassium current. Neuropharmacology. 2020;177:108248.

    Article  PubMed  CAS  Google Scholar 

  34. Nakamura Y, Yahiro T, Fukushima A, Kataoka N, Hioki H, Nakamura K. Prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling. Sci Adv. 2022;8:eadd5463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Machado NLS, Saper CB. Genetic identification of preoptic neurons that regulate body temperature in mice. Temperature. 2022;9:14–22.

    Article  Google Scholar 

  36. Yang WZ, Du X, Zhang W, Gao C, Xie H, Xiao Y, et al. Parabrachial neuron types categorically encode thermoregulation variables during heat defense. Sci Adv. 2020;6:eabb9414.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Oka T, Oka K, Kobayashi T, Sugimoto Y, Ichikawa A, Ushikubi F, et al. Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EP3 receptors. J Physiol. 2003;551:945–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lazarus M, Yoshida K, Coppari R, Bass CE, Mochizuki T, Lowell BB, et al. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci. 2007;10:1131–3.

    Article  PubMed  CAS  Google Scholar 

  39. Vasilache AM, Andersson J, Nilsberth C. Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region. Neurosci Lett. 2007;423:179–83.

    Article  PubMed  CAS  Google Scholar 

  40. Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem. 2007;282:11613–7.

    Article  PubMed  CAS  Google Scholar 

  41. Bird GC, Lash LL, Han JS, Zou X, Willis WD, Neugebauer V. Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol. 2005;564:907–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Evans DI, Jones RS, Woodhall G. Differential actions of PKA and PKC in the regulation of glutamate release by group III mGluRs in the entorhinal cortex. J Neurophysiol. 2001;85:571–9.

    Article  PubMed  CAS  Google Scholar 

  43. Pugh PC, Jayakar SS, Margiotta JF. PACAP/PAC1R signaling modulates acetylcholine release at neuronal nicotinic synapses. Mol Cell Neurosci. 2010;43:244–57.

    Article  PubMed  CAS  Google Scholar 

  44. Hampson RE, Evans GJ, Mu J, Zhuang SY, King VC, Childers SR, et al. Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium “A-current” in cultured rat hippocampal neurons. Life Sci. 1995;56:2081–8.

    Article  PubMed  CAS  Google Scholar 

  45. Zhao X, Zhang Y, Qin W, Cao J, Zhang Y, Ni J, et al. Serotonin type-1D receptor stimulation of A-type K+ channel decreases membrane excitability through the protein kinase A- and B-Raf-dependent p38 MAPK pathways in mouse trigeminal ganglion neurons. Cell Signal. 2016;28:979–88.

    Article  PubMed  CAS  Google Scholar 

  46. Norris AJ, Shaker JR, Cone AL, Ndiokho IB, Bruchas MR. Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses. Elife. 2021;10:e60779.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Yang WZ, Xie HC, Du X, Zhou Q, Xiao Y, Zhao ZD, et al. A parabrachial-hypothalamic parallel circuit governs cold defense in mice. Nat Commun. 2023;14:4924.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Yahiro T, Kataoka N, Nakamura K. Two ascending thermosensory pathways from the lateral parabrachial nucleus that mediate behavioral and autonomous thermoregulation. J Neurosci. 2023;43:5221–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Osterhout JA, Kapoor V, Eichhorn SW, Vaughn E, Moore JD, Liu D, et al. A preoptic neuronal population controls fever and appetite during sickness. Nature. 2022;606:937–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Jian-hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tian-hui He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan-ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-min Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong-jing Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiao-feng Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Si-hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan-lin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wen Z. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Wen Z. Yang or Jie Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 45, 1832–1847 (2024). https://doi.org/10.1038/s41401-024-01289-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-024-01289-6

Keywords

Search

Advanced search

Quick links