Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

Abstract

Background Ephrin‐B2/EphB receptor signaling contributes to persistent pain states such as postinflammatory and neuropathic pain. Visceral hypersensitivity (VHS) is a major mechanism underlying abdominal pain in patients with irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) in remission, but the underlying pathophysiology remains unclear. Here, we evaluated the spinal ephrin‐B2/EphB pathway in VHS in 2 murine models of VHS, that is, postinflammatory TNBS colitis and maternal separation (MS). Methods Wild‐type (WT) mice and mice lacking ephrin‐B2 in Nav1.8 nociceptive neurons (cKO) were studied. VHS was induced by: 1. intracolonic instillation of TNBS or 2. water avoidance stress (WAS) in mice that underwent maternal separation (MS). VHS was assessed by quantifying the visceromotor response (VMRs) during colorectal distention. Colonic tissue and spinal cord were collected for histology, gene, and protein expression evaluation. Key Results In WT mice, but not cKO mice, TNBS induced VHS at day 14 after instillation, which returned to baseline perception from day 28 onwards. In MS WT mice, WAS induced VHS for up to 4 weeks. In cKO however, visceral pain perception returned to basal level by week 4. The development of VHS in WT mice was associated with significant upregulation of spinal ephrin‐B2 and EphB1 mRNA expression or protein levels in the TNBS model and upregulation of spinal ephrin‐B2 protein in the MS model. No changes were observed in cKO mice. VHS was not associated with persistent intestinal inflammation. Conclusions and Inferences Overall, our data indicate that the ephrin‐B2/EphB1 spinal signaling pathway is involved in VHS and may represent a novel therapeutic target.

Blockade of Erythropoietin-Producing Human Hepatocellular Carcinoma Receptor B1 in Spinal Dorsal Horn Alleviates Visceral Pain in Rats

“…By using a visceral hyperalgesia model induced by intracolonic TNBS, this experiment showed that intrathecal administration of EphB1 receptor blocking reagent significantly alleviated visceral hyperalgesia with downregulation of spinal EphB1 expression. This is in accord with the results of a recent study [ 33 ], in which visceral hyperalgesia induced by intracolonic TNBS in wild-type mice did not occur in the ephrinB2 knockout mice.…”

“…In each animal, colorectal distension (CRD) was carried out 17 days after intracolonic injection of TNBS or vehicle, as previously described [ 4 , 33 , 38 ]. In brief, a latex double-lumen catheter was attached to a balloon dilator with a diameter of 5 mm.…”

“…However, the importance of this signaling pathway is mainly identified in the development of somatic pain. Up to now, only a few studies are focused on the involvement of ephrinB2/EphB1 signaling pathway in the pathogenesis of visceral pain [ 32 , 33 ]. For example, a previous work using pelvic-urethra-related pain model found that ephrinB2 potentiated the pelvic-urethra reflex due to phosphorylation of EphB1 and/or 2 via the Src kinase [ 32 ].…”

“…For example, a previous work using pelvic-urethra-related pain model found that ephrinB2 potentiated the pelvic-urethra reflex due to phosphorylation of EphB1 and/or 2 via the Src kinase [ 32 ]. Recently, another study using ephrinB2 knockout animals demonstrated that both ephrinB2 and EphB1 played important roles in 2, 4, 6-trinitrobenzene sulfonic acid- (TNBS-) induced chronic (postinflammatory) visceral pain, but only ephrinB2 was involved in the development of stress-induced visceral pain [ 33 ]. Most important, it remains unclear whether administration of specific blockers to interrupt the phosphorylation of EphB1 and/or expression of ephrinB2 would attenuate visceral pain.…”

Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice

“…One study demonstrated that MS caused visceral hypersensitivity by activating brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB)protein kinase Mζ (PKMζ) signaling in the thoracolumbar spinal cord of adult rats (Fan et al, 2020). In addition, sensitization and upregulation of microglial toll-like receptor 4 (TLR4) signaling activity in the PVN (Tang et al, 2017), ephrin-B2/EphB1 spinal signaling pathway (Theofanous et al, 2020), and nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signaling (Wong et al, 2019) were involved in MS-induced visceral hypersensitivity. Moreover, various important signaling molecule dysfunctions were also involved in MS-induced visceral hypersensitivity, such as elevated expression of Nesfatin-1 in the dorsal raphe nucleus (DRN) (Zhang et al, 2018).…”