Electroacupuncture Attenuates Visceral Hypersensitivity by Inhibiting JAK2/STAT3 Signaling Pathway in the Descending Pain Modulation System

Abstract

Electroacupuncture (EA) has been used for treating visceral hypersensitivity (VH). However, the underlying molecular mechanism remains unclear. This study was aim to testify the effect of EA on ileitis-provoked VH, and to confirm whether EA attenuates VH through Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway in the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal cord dorsal horn (SCDH) axis. Methods:Goats were anesthetized and laparotomized for injecting 2,4,6-trinitro-benzene-sulfonic acid (TNBS)-ethanol solution (30 mg TNBS dissolved in 40% ethanol) into the ileal wall to induce VH. EA was treated for 30 min from day 7, then every 3 days for six times. VH was assessed by visceromotor response (VMR) and pain behavior response to 20, 40, 60, 80, and 100 mmHg colorectal distension pressures at day 7, 10, 13, 16, 19, and 22. The spinal cord in the eleventh thoracic vertebra and the brain were collected at day 22. The protein and mRNA levels of IL-6, JAK2, and STAT3 in the SCDH were detected with western blot and qPCR, respectively. The distribution of these substances was observed with immunohistochemistry in the ventrolateral PAG (vlPAG), RVM (mainly the nucleus raphe magnus, NRM), SCDH, the nucleus tractus solitaries (NTS) and the dorsal motor nucleus of vagi (DMV).Results: Goats administered with TNBS-ethanol solution showed diarrhea, enhanced VMR and pain behavior response, and increased IL-6, phosphorylated JAK2 and STAT3 (pJAK2 and pSTAT3) in the vlPAG, NRM, NTS and DMV, and their protein and mRNA levels in the SCDH. EA relieved diarrhea, VMR and pain behavior response, decreased IL-6, pJAK2 and pSTAT3 levels in the vlPAG, NRM, SCDH, NTS, and DMV except for pSTAT3 in the DMV, but did not affect mRNA level of these three substances in the SCDH.Conclusion: EA attenuates VH probably through inhibiting JAK2/STAT3 signaling pathway in the PAG-RVM-SCDH axis.

Electroacupuncture Inhibits the Activity of Astrocytes in Spinal Cord in Rats with Visceral Hypersensitivity by Inhibiting P2Y1 Receptor‐Mediated MAPK/ERK Signaling Pathway

“…A recent systematic review and meta-analysis of randomized controlled trials (RCT) of clinical acupuncture for IBS confirmed the effectiveness of traditional Chinese medicine acupuncture for IBS [2][3][4][5]. Electroacupuncture (EA) can inhibit visceral injury responses at multiple levels [6,7]. EA at body surface acupoints can inhibit visceral injury response at multiple nerve levels with the largest inhibitory effect on spinal dorsal horn [8].…”

Electroacupuncture intervention of visceral hypersensitivity is involved in PAR-2-activation and CGRP-release in the spinal cord

“…Likewise, CD pediatric patients coexisting functional GI disorders showed rectal hypersensitivity 2 . Our earlier studies 32,40,42 also reported VH in response to graded CRD in rats and goats with TNBS-induced ileitis. Researches demonstrate that VH across the organs is due to the central sensitization of spinal cord neurons receiving convergent input from different organs 69,70 or descending bulbospinal inhibition of sacral dorsal horn neurons in response to chronic intestinal tissue irritation 71 .…”

“…Recently, MPO activity has been assayed as a biochemical indicator of inflammation. It is observed in the neutrophils and their oxidative products, particularly involved in the tissue damage process during the acute stage of 32 reported that the MPO concentration in TNBS-injected ileum of the goats was increased on day 7 rather than on day 22. Increasing sets of evidence show the importance of PAR-2 both in gastroenteritis 11,45,46 and inflammatory condition of the central nerve system 17,47,48 .…”

“…Furthermore, EA at ST36 relieved the visceral sensitivity and the gastrointestinal motility disorder in rats of IBS model 77 . Recently, Wan et al 32 reported that EA at ST36 reduced pain behavioral manifestations and VH in goats. In this study, EA application at bilateral ST36 reduced the TNBSinduced ileitis and VMR to CRD of goats, which is similar to the findings of the earlier study 32 .…”

Electroacupuncture Relieves Visceral Hypersensitivity by Inactivating Protease‐Activated Receptor 2 in a Rat Model of Postinfectious Irritable Bowel Syndrome

“…The analgesic effect of EA application in VH has been extensively reported [ 27 – 29 ], and therefore the molecular mechanisms involved in this effect are attracting more attention. Previous studies have indicated that the endogenous opioid pathway in the periphery [ 27 , 28 ], the JAK2/STAT3 signaling pathway in the PAG-RVM-SCDH axis [ 29 ], the corticotropin-releasing hormone in the colon, spinal cord, and hypothalamus [ 15 ], and other pathways are all involved in mediating the effects of EA on VH. In agreement with previous research by our group [ 30 ], several studies indicate that EA attenuates VH via reduction of both colonic enterochromaffin cell number and 5-HT concentration in the brain-gut axis [ 29 , 31 – 33 ].…”