Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation
Neonatal maternal separation (MS) is a major early life stress that increases the risk of emotional disorders, visceral pain perception and other brain dysfunction. Elevation of toll-like receptor 4 (TLR4) signaling in the paraventricular nucleus (PVN) precipitates early life colorectal distension (...
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Frontiers Media S.A.
2017-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00309/full |
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| author | Hui-Li Tang Hui-Li Tang Gongliang Zhang Ning-Ning Ji Lei Du Bin-Bin Chen Rong Hua Yong-Mei Zhang |
| author_facet | Hui-Li Tang Hui-Li Tang Gongliang Zhang Ning-Ning Ji Lei Du Bin-Bin Chen Rong Hua Yong-Mei Zhang |
| author_sort | Hui-Li Tang |
| collection | DOAJ |
| description | Neonatal maternal separation (MS) is a major early life stress that increases the risk of emotional disorders, visceral pain perception and other brain dysfunction. Elevation of toll-like receptor 4 (TLR4) signaling in the paraventricular nucleus (PVN) precipitates early life colorectal distension (CRD)-induced visceral hypersensitivity and pain in adulthood. The present study aimed to investigate the role of TLR4 signaling in the pathogenesis of postnatal MS-induced visceral hypersensitivity and pain during adulthood. The TLR4 gene was selectively knocked out in C57BL/10ScSn mice (Tlr4-/-). MS was developed by housing the offspring alone for 6 h daily from postnatal day 2 to day 15. Visceral hypersensitivity and pain were assessed in adulthood. Tlr4+/+, but not Tlr4-/-, mice that had experienced neonatal MS showed chronic visceral hypersensitivity and pain. TLR4 immunoreactivity was observed predominately in microglia in the PVN, and MS was associated with an increase in the expression of protein and/or mRNA levels of TLR4, corticotropin-releasing factor (CRF), CRF receptor 1 (CRFR1), tumor necrosis factor-α, and interleukin-1β in Tlr4+/+ mice. These alterations were not observed in Tlr4-/- mice. Local administration of lipopolysaccharide, a TLR4 agonist, into the lateral cerebral ventricle elicited visceral hypersensitivity and TLR4 mRNA expression in the PVN, which could be prevented by NBI-35965, an antagonist to CRFR1. The present results indicate that neonatal MS induces a sensitization and upregulation of microglial TLR4 signaling activity, which facilitates the neighboring CRF neuronal activity and, eventually, precipitates visceral hypersensitivity in adulthood.Highlights(1)Neonatal MS does not induce chronic visceral hypersensitivity and pain in Tlr4-/- mice.(2)Neonatal MS increases the expression of TLR4 mRNA, CRF protein and mRNA, CRFR1 protein, TNF-α protein, and IL-1β protein in Tlr4+/+ mice.(3)TLR4 agonist LPS (i.c.v.) elicits visceral hypersensitivity and TLR4 mRNA expression in the PVN. |
| first_indexed | 2024-12-11T13:51:23Z |
| format | Article |
| id | doaj.art-1ffced362d274533a6e7059c7527ce5a |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T13:51:23Z |
| publishDate | 2017-05-01 |
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| spelling | doaj.art-1ffced362d274533a6e7059c7527ce5a2022-12-22T01:04:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-05-01810.3389/fphar.2017.00309253753Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal SeparationHui-Li Tang0Hui-Li Tang1Gongliang Zhang2Ning-Ning Ji3Lei Du4Bin-Bin Chen5Rong Hua6Yong-Mei Zhang7Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityXuzhou, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Soochow UniversitySuzhou, ChinaDepartment of Pharmacology, College of Basic Medical Sciences, Anhui Medical UniversityHefei, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityXuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityXuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityXuzhou, ChinaDepartment of Emergency, Affiliated Hospital of Xuzhou Medical UniversityXuzhou, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityXuzhou, ChinaNeonatal maternal separation (MS) is a major early life stress that increases the risk of emotional disorders, visceral pain perception and other brain dysfunction. Elevation of toll-like receptor 4 (TLR4) signaling in the paraventricular nucleus (PVN) precipitates early life colorectal distension (CRD)-induced visceral hypersensitivity and pain in adulthood. The present study aimed to investigate the role of TLR4 signaling in the pathogenesis of postnatal MS-induced visceral hypersensitivity and pain during adulthood. The TLR4 gene was selectively knocked out in C57BL/10ScSn mice (Tlr4-/-). MS was developed by housing the offspring alone for 6 h daily from postnatal day 2 to day 15. Visceral hypersensitivity and pain were assessed in adulthood. Tlr4+/+, but not Tlr4-/-, mice that had experienced neonatal MS showed chronic visceral hypersensitivity and pain. TLR4 immunoreactivity was observed predominately in microglia in the PVN, and MS was associated with an increase in the expression of protein and/or mRNA levels of TLR4, corticotropin-releasing factor (CRF), CRF receptor 1 (CRFR1), tumor necrosis factor-α, and interleukin-1β in Tlr4+/+ mice. These alterations were not observed in Tlr4-/- mice. Local administration of lipopolysaccharide, a TLR4 agonist, into the lateral cerebral ventricle elicited visceral hypersensitivity and TLR4 mRNA expression in the PVN, which could be prevented by NBI-35965, an antagonist to CRFR1. The present results indicate that neonatal MS induces a sensitization and upregulation of microglial TLR4 signaling activity, which facilitates the neighboring CRF neuronal activity and, eventually, precipitates visceral hypersensitivity in adulthood.Highlights(1)Neonatal MS does not induce chronic visceral hypersensitivity and pain in Tlr4-/- mice.(2)Neonatal MS increases the expression of TLR4 mRNA, CRF protein and mRNA, CRFR1 protein, TNF-α protein, and IL-1β protein in Tlr4+/+ mice.(3)TLR4 agonist LPS (i.c.v.) elicits visceral hypersensitivity and TLR4 mRNA expression in the PVN.http://journal.frontiersin.org/article/10.3389/fphar.2017.00309/fullneonatal maternal separationvisceral hypersensitivityPVNTLR4CRF |
| spellingShingle | Hui-Li Tang Hui-Li Tang Gongliang Zhang Ning-Ning Ji Lei Du Bin-Bin Chen Rong Hua Yong-Mei Zhang Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation Frontiers in Pharmacology neonatal maternal separation visceral hypersensitivity PVN TLR4 CRF |
| title | Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation |
| title_full | Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation |
| title_fullStr | Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation |
| title_full_unstemmed | Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation |
| title_short | Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation |
| title_sort | toll like receptor 4 in paraventricular nucleus mediates visceral hypersensitivity induced by maternal separation |
| topic | neonatal maternal separation visceral hypersensitivity PVN TLR4 CRF |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00309/full |
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