Managing disorders associated with altered perception of abdominal pain remains a major challenge in healthcare. This is particularly true with silent inflammatory bowel disease (IBD), a condition in which individuals with active disease experience little to no concomitant abdominal pain. Silent IBD is common, affecting a third or more of these patients, and can be seen in both major forms of IBD, Crohn?s disease (CD) and ulcerative colitis (UC). Silent IBD is also very impactful, as these individuals are more than twice as likely to develop serious complications (including strictures, fistulae and abscesses) and to be hospitalized. Unfortunately, currently available diagnostic strategies are limited due to inefficacy, expense and/or practicality. A refined understanding of the mechanisms underlying silent IBD would allow us to develop more effective methods to screen for patients at risk for this condition and could provide insight into novel targets that could be utilized to manage conditions associated with chronic abdominal pain. There is evidence to suggest that voltage-gated sodium channels (VGSC?s) could play a particularly critical role in the development of silent IBD. Previous studies have implicated certain subtypes of these channels as major contributors to transmission of peripheral somatosensory and visceral pain signals. Using targeted exome sequencing in a small IBD cohort, we found that homozygosity for one genetic variant of Nav1.8 (rs6795970; G>A; A1073V) was more common in silent IBD patients. This is notable as one prior study linked this particular polymorphism to hyposensitivity to somatosensory pain stimuli. We hypothesize that Nav1.8 is critical for mediating visceral pain perception and that rs6795970 leads to its dysfunction, resulting in an anti-nociceptive phenotype in IBD. In order to test this hypothesis, we propose to: a) evaluate the frequency of the polymorphism, rs6795970, within larger cohorts of healthy controls, CD and UC patients phenotyped for pain and disease activity, b) assess for changes in visceral and somatic sensation associated with this polymorphism, using barostatic rectal distension and quantitative sensory testing techniques, and c) evaluate for changes in biophysical function of intestinal sensory afferent neurons and pharmacological function of sensory neuron derived cells expressing the mutant channel associated with this polymorphism. These studies are essential as they could identify an objective biomarker to identify patients at risk of developing silent IBD and may provide critical insight into new diagnostic and therapeutic strategies to manage disorders associated with alterations of abdominal pain.
Silent inflammatory bowel disease (IBD) is a common and poorly understood phenomenon associated with serious complications and increased healthcare resource utilization. We plan to examine the potential role that the voltage-gated sodium channel, NaV1.8, and the functionally relevant, associated polymorphism, rs6795970, play in this condition. Findings from this proposal could be used to develop more objective diagnostic tools to identify patients at risk for silent IBD, and new management strategies to help individuals suffering with disorders associated with altered abdominal pain perception.