Melatonin attenuated chronic visceral pain by reducing Nav1.8 expression and nociceptive neuronal sensitization.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, and its specific pathogenesis is still unclear. We have previously reported that TTX-resistant (TTX-R) sodium channels in colon-specific dorsal root ganglion (DRG) neurons were sensitized in a rat model of visceral hypersensitivity induced by neonatal colonic inflammation (NCI). However, the detailed molecular mechanism for activation of sodium channels remains unknown. This study was designed to examine roles for melatonin (MT) in sensitization of sodium channels in NCI rats. METHODS: Colorectal distention (CRD) in adult male rats as a measure of visceral hypersensitivity. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch clamp configurations. Western blot and Immunofluorescence were employed to detect changes in expression of Nav1.8 and MT2. RESULTS: The results showed that rats exhibited visceral hypersensitivity after NCI treatment. Intrathecal application of melatonin significantly increased the threshold of CRD in NCI rats with a dose-dependent manner, but has no role in the control group. Whole-cell patch clamp recording showed that melatonin remarkably decreased the excitability and the density of TTX-R sodium channel in DRG neurons from NCI rats. The expression of MT2 receptor at the protein level was markedly lower in NCI rats. 8MP, an agonist of MT2 receptor, enhanced the distention threshold in NCI rats. Application of 8MP reversed the enhanced hypersensitivity of DRG neurons from NCI rats. 8MP also reduced TTX-R sodium current density and modulated dynamics of TTX-R sodium current activation. CONCLUSIONS: These data suggest that sensitization of sodium channels of colon DRG neurons in NCI rats is most likely mediated by MT2 receptor, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.

Exploring the Interrelationships between Public Health, Fiscal Decentralization, and Local Government Debt in China.

This paper investigates the interrelationships among local government debt, fiscal decentralization, and public health. The investigation begins by constructing a theoretical model to analyze the inherent connections between these variables. Subsequently, an empirical analysis is conducted using data from China between 2015 and 2021. The findings demonstrate a bidirectional relationship between fiscal decentralization, local government debt, and public health. Specifically, it is observed that an increase in local government debt has adverse effects on both fiscal decentralization and public health, while fiscal decentralization has a positive impact on public health. These insights are consistently validated through rigorous regression methodologies, affirming the robustness and significance of these relationships.

Nonlinear Relationship between Financial Development and CO2 Emissions-Based on a PSTR Model.

The contradiction between financial development and environmental pollution has become increasingly prominent with economic development. The discovery of the link between financial development and carbon dioxide emissions will aid in the development of solutions to this problem. This paper uses a panel smooth transition regression (PSTR) model to examine the impact of financial development on carbon dioxide emissions using panel data from 28 Chinese provinces from 2005 to 2021. The PSTR model can solve the problem of minimizing potential outliers ignored in the previous literature, while taking into account the endogeneity and heterogeneity of the model and obtaining more reliable results. According to the findings, financial development has a nonlinear effect on carbon dioxide emissions. Furthermore, the positive effect of financial development on carbon dioxide emissions occurs via the scale and structural effects, while the negative effect occurs via the technological effect, which takes up more space. Moreover, financial added value and the financial scale demonstrate a smooth transition, while financial efficiency and foreign direct investment demonstrate a positive influence.