Melatonin attenuated chronic visceral pain by reducing Na_v1.8 expression and nociceptive neuronal sensitization

Abstract

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 Na<sub>v</sub>1.8 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. 8-MP, an agonist of MT2 receptor, enhanced the distention threshold in NCI rats. Application of 8-MP reversed the enhanced hypersensitivity of DRG neurons from NCI rats. 8-MP 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.

The double burden of malnutrition and environmental enteric dysfunction as potential factors affecting gut-derived melatonin in children under adverse environments

“…As far as we know the scientific literature on melatonin and EED/DBM is still missing, therefore it is difficult to distinct the underlying effects and mechanisms of melatonin's efficacy in such conditions (EED/DBM) comparing to other well-recognized gastrointestinal diseases. Up to date, beneficial effects of melatonin supplementation has been found in animal models of obesity and metabolic syndrome ( 38 ), intestinal bowel disease ( 39 ) and irritable bowel syndrome ( 40 ), mostly by antioxidant, anti-inflammatory and regulatory intestinal microbiota's effects. We expect that some of the underlying mechanisms of melatonin's protective mechanisms on these conditions also happen to EED/DBM.…”

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice

“… 9 – 11 Despite extensive research, the exact molecular mechanisms remain incompletely elucidated. 12 Previous studies have shown that chronic visceral pain in IBS patients may stem from psychological abnormalities linked to adverse childhood experiences. 10 , 13 To further explore this, neonatal maternal deprivation (NMD) serves as a well-established early life stress model, inducing chronic visceral pain in adult mice.…”

Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons

“…Notably, there is a particular focus on its capacity to relieve chronic pain by involving the MT2 receptor . By applying MLT intrathecally, nociceptive neuronal sensitization in dorsal root ganglion (DRG) neurons is reduced, leading to the attenuation of chronic pain, with the mediation of the MT2 receptor . On the other hand, a growing body of evidence highlights MLT’s potential to enhance the efficacy of chemotherapy while mitigating its adverse effects .…”

“…2 By applying MLT intrathecally, nociceptive neuronal sensitization in dorsal root ganglion (DRG) neurons is reduced, leading to the attenuation of chronic pain, with the mediation of the MT2 receptor. 4 On the other hand, a growing body of evidence highlights MLT's potential to enhance the efficacy of chemotherapy while mitigating its adverse effects. 5 Despite its effectiveness as a cancer treatment, chemotherapy is limited by the significant side effects and causes, particularly peripheral neuropathic pain, by inducing nociceptive neuronal sensitization in DRG neurons.…”