HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain
Abstract Background Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain....
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | The Journal of Headache and Pain |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10194-022-01475-z |
| _version_ | 1798038983342555136 |
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| author | Yu Du Ceng-Lin Xu Jie Yu Keyue Liu Shi-Da Lin Ting-Ting Hu Feng-Hui Qu Fang Guo Guo-Dong Lou Masahiro Nishibori Wei-Wei Hu Zhong Chen Shi-Hong Zhang |
| author_facet | Yu Du Ceng-Lin Xu Jie Yu Keyue Liu Shi-Da Lin Ting-Ting Hu Feng-Hui Qu Fang Guo Guo-Dong Lou Masahiro Nishibori Wei-Wei Hu Zhong Chen Shi-Hong Zhang |
| author_sort | Yu Du |
| collection | DOAJ |
| description | Abstract Background Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. Methods Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. Results Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. Conclusion These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity. |
| first_indexed | 2024-04-11T21:47:39Z |
| format | Article |
| id | doaj.art-410487cbb93f4a578403216743084fa0 |
| institution | Directory Open Access Journal |
| issn | 1129-2369 1129-2377 |
| language | English |
| last_indexed | 2024-04-11T21:47:39Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | The Journal of Headache and Pain |
| spelling | doaj.art-410487cbb93f4a578403216743084fa02022-12-22T04:01:23ZengBMCThe Journal of Headache and Pain1129-23691129-23772022-08-0123112010.1186/s10194-022-01475-zHMGB1 in the mPFC governs comorbid anxiety in neuropathic painYu Du0Ceng-Lin Xu1Jie Yu2Keyue Liu3Shi-Da Lin4Ting-Ting Hu5Feng-Hui Qu6Fang Guo7Guo-Dong Lou8Masahiro Nishibori9Wei-Wei Hu10Zhong Chen11Shi-Hong Zhang12Department of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityDepartment of Pharmacology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineDepartment of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityDepartment of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Pharmacology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineDepartment of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityDepartment of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of MedicineAbstract Background Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. Methods Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. Results Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. Conclusion These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity.https://doi.org/10.1186/s10194-022-01475-zHMGB1NeuroinflammationmPFCNeuropathic painComorbid mood disordersAnxiety |
| spellingShingle | Yu Du Ceng-Lin Xu Jie Yu Keyue Liu Shi-Da Lin Ting-Ting Hu Feng-Hui Qu Fang Guo Guo-Dong Lou Masahiro Nishibori Wei-Wei Hu Zhong Chen Shi-Hong Zhang HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain The Journal of Headache and Pain HMGB1 Neuroinflammation mPFC Neuropathic pain Comorbid mood disorders Anxiety |
| title | HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain |
| title_full | HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain |
| title_fullStr | HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain |
| title_full_unstemmed | HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain |
| title_short | HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain |
| title_sort | hmgb1 in the mpfc governs comorbid anxiety in neuropathic pain |
| topic | HMGB1 Neuroinflammation mPFC Neuropathic pain Comorbid mood disorders Anxiety |
| url | https://doi.org/10.1186/s10194-022-01475-z |
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