Visceral Hypersensitivity in Irritable Bowel Syndrome: The role of spinal cord signaling

Abdominal pain is one of the most difficult to treat symptoms in patients suffering from Functional Gastro-Intestinal Disorders (FGIDs). Recent evidence shows that visceral hypersensitivity (VHS), represents an important underlying mechanism. The most common and most studied FGID is Irritable Bowel Syndrome (IBS), characterized by chronic discomfort and abdominal pain associated with altered defecation in the absence of an organic cause. 40-60 % of IBS patients suffer from VHS. The three main triggers for the development of chronic VHS are an episode of bacterial gastroenteritis, psychological stress and inflammation. Indeed, gastrointestinal infections resulting from bacterial, viral, and parasitic pathogens predispose to post-infectious IBS (PI-IBS) in about 30% of individuals even though the initial infection is fully cleared. Repeated exposure to psychological stress can also trigger the onset of IBS and exacerbates pre-existing IBS symptoms. Preclinical models confirmed that acute intestinal inflammation, as seen in ulcerative colitis (UC) patients, can indeed result in long term visceral hypersensitivity. The exact mechanism involved in VHS remains unclear but several preclinical studies showed that increased numbers and/or potentiation of nociceptors on afferent sensory neurons may lead to chronic VHS. The mechanisms underlying neuronal sensitization are not fully understood. In line, the receptor tyrosine kinase EphB2 has drawn recent attention with the discovery that its activation increases inflammatory and neuropathic pain. The Eph receptor family, of which EphB2 is a member, consists of 2 classes of receptors, designated A and B, which are distinguished by their extracellular domain sequence homologies. EphB ligands, known as ephrins, are also divided into two classes, soluble ephrinA and transmembrane ephrinB. The EphB2 receptor binds to Ephrin-B1, Ephrin-B2, and Ephrin-B3 ligands. The interaction of EphB2 receptors and ephrins can signal bidirectionally into EphB2-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). Recent research learnt that ephrin-B2 ligand on presynaptic sensory afferent fibers arising from the dorsal root ganglia (DRG) interact with EphB2 receptors on spinal cord neurons to transmit pain sensation to the central nervous systemTo what extent EphB2-ephrin-B2 signaling contributes to increased abdominal pain sensitivity remains unclear. Based on recent studies we hypothesize that an acute gastrointestinal insult (infection, inflammation or stress) will trigger EphB2-ephrin-B2 signaling in the spinal cord in a subgroup of patients, thereby transmitting more pain signals to the brain and leading to persistent aberrant abdominal pain perception (Objective 1).Also, of interest, in recent years, small non-coding RNA sequences referred to as miRNAs, have been shown to regulate EphB2 expression and have attracted intense research efforts in targeted therapy. Based on these observations, the control of EphB2 expression and activity seems to be regulated in a cell specific manner by miRNAs. This cell-specific epigenetic control mechanism has not been studied in sensory neurons with respect to visceral pain perception, and thus will be investigated in Objective 2.Finally, accumulating evidence from the central nervous system showed that EphB2 pathway activation promotes the phosphorylation of N-methyl-D-aspartic acid receptors (NMDAR), thereby recruiting active NMDARs to the excitatory synapses and potentially increasing pain perception. Indeed, it has been shown that mice lacking ephrin-B2 in sensory neurons have an attenuated neuropathic pain response that correlates with diminished tyrosine phosphorylation of NMDA receptor subunit NR2B in the dorsal horn. Abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions (Huntington's, Parkinson's, Alzheimer's diseases, epilepsy, neuropathic pain, schizophrenia, and mood disorders). However, NMDARs can also mediate peripheral sensitization and visceral pain. In particular, the NMDAR subunit NR2B appears important for nociception, thus leading to the possibility that NR2B-selective antagonists may be useful in the treatment of aberrant visceral pain perception. So the role of NMDAR and its relationship to the EphB2 pathway in the development of visceral hypersensitivity will also be investigated in Objective 2.

Publication year:2020

Accessibility:Embargoed