Dataset Information

Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α.

ABSTRACT:

Background

Visceral hypersensitivity (VH) is one of the most common causes of irritable bowel syndrome (IBS). The anti-hyperalgesic effects of metabotropic glutamate receptor 8 (mGluR8) has been identified in the central nervous system (CNS). However, whether this receptor has a similar function in the gastrointestinal tract has not been well studied. The present study aimed to explore the role of this receptor in a visceral hypersensitivity-related IBS rat model.

Methods

Neonatal rats were separated from their mothers for 3 hours daily from postnatal day 2 to day 14 to establish neonatal maternal separation (NMS) models. The mGluR8 agonist (S)-3,4-DCPG (10 mg/kg) and the mGluR8 antagonist (RS)-α- methylserine-O-phosphate (MSOP) (10 mg/kg) were used to examine the role of mGLuR8 in the NMS rats. The expression of mGluR8, related inflammatory factors, and inflammatory signal pathways were assessed in colon tissues.

Results

Our data showed that mGluR8 expression was increased in the colonic mucosa of NMS rats compared to controls. In addition, selective activation of mGluR8 ameliorated visceral hypersensitivity, whereas antagonization of mGluR8 aggravated visceral hypersensitivity. Treatment with (S)-3,4-DCPG (10 mg/kg) reduced the expression of myeloperoxidase (MPO) in intestinal mucosa of NMS rats. Furthermore, activating mGluR8 reduced the expression of tumor necrosis factor-α (TNF-α), whereas antagonizing mGluR8 promoted that. The expressions of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) did not significantly change upon activation or antagonization of mGluR8 receptor.

Conclusions

The activation of mGluR8 receptor ameliorates visceral hypersensitivity in NMS rats, and the underlying mechanisms may be associated with the inhibition of TNF-α and the suppression of colonic inflammatory response.

SUBMITTER: Wang X

PROVIDER: S-EPMC9929757 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α.

Wang Xiaobo X Shao Limei L Hua Hongjun H Chen Yanping Y

Annals of translational medicine 20230101 2

<h4>Background</h4>Visceral hypersensitivity (VH) is one of the most common causes of irritable bowel syndrome (IBS). The anti-hyperalgesic effects of metabotropic glutamate receptor 8 (mGluR8) has been identified in the central nervous system (CNS). However, whether this receptor has a similar function in the gastrointestinal tract has not been well studied. The present study aimed to explore the role of this receptor in a visceral hypersensitivity-related IBS rat model.<h4>Methods</h4>Neonatal ...[more]

PMID: 36819583

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Project 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.

Project description:Early adverse life events (EALs), such as maternal separation (MS), can cause visceral hypersensitivity, which is thought to be a key pathophysiological mechanism of irritable bowel syndrome (IBS). Previous studies mainly focused on EALs-induced visceral hypersensitivity in adulthood but did not consider that it may have occurred in the preadult period. We previously found that rats who experienced MS suffered from visceral hypersensitivity starting from the post-weaning period. Moreover, the hippocampus is considered to be critical in regulating the formation of visceral hypersensitivity induced by MS. But the underlying mechanisms throughout different life periods are unclear. In this study, behavioral tests, RNA-seq, lentiviral interference, and molecular biology techniques were applied to investigate the molecular mechanism in the hippocampus underlying MS-induced long-lasting visceral hypersensitivity. It was found that both visceral sensitivity and anxiety-like behaviors were significantly increased in MS rats in post-weaning, prepubertal, and adult periods, especially in the prepubertal period. Subsequently, RNA-seq targeting the hippocampus identified that the expression level of Netrin-1 was significantly increased in all periods, which was further confirmed by quantitative real-time PCR and Western blot. Knocking-down hippocampal Netrin-1 in the post-weaning period by lentivirus interference alleviated visceral hypersensitivity and anxiety-like behaviors of MS rats in the later phase of life. In addition, deleted in colorectal cancer (DCC), instead of neogenin-1(Neo-1) or uncoordinated (UNC5), was proved to be the specific functional receptor of Netrin-1 in regulating visceral hypersensitivity, whose upregulation may result in the most severe symptoms in the prepubertal period. Furthermore, the activation of the Netrin-1/DCC pathway could enhance long-term potentiation (LTP) in the hippocampus, probably via recruitment of the AMPA receptor subunit GluA1, which finally resulted in the formation of visceral hypersensitivity. These novel findings suggest that long-lasting over-expression of Netrin-1 can mediate visceral hypersensitivity and anxiety disorder from the post-weaning period to adulthood by activating DCC/GluA1 pathway in the hippocampus. Moreover, early intervention of Netrin-1 in the post-weaning period could lead to significant symptom relief afterward, which provides evidence that the Netrin-1/DCC/GluA1 signaling pathway may be a potential therapeutic target for the treatment of visceral hypersensitivity in clinics.

Project description:Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.

Dataset Information

Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α.

Background

Methods

Results

Conclusions

Publications

Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α.

Similar Datasets

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