Assessing the Role of the Transient Receptor Potential Melastatin 3 (TRPM3) Ion Channel in Visceral Sensation

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King, James
abdominal pain , trp channels , inflammatory bowel disease , ion channels , peripheral sensitization
Abdominal pain is a significant clinical problem impacting many individuals including patients with inflammatory bowel disease (IBD). Current therapeutics for IBD-related pain include opioids which are addictive and associated with increased mortality in IBD patients. Thus, novel mechanisms for pain relief should be investigated to identify safe and efficacious treatments. Transient receptor potential (TRP) channels represent a therapeutic target for abdominal pain that may have fewer side effects and potentially provide efficacious relief from pain. Various TRP channels contribute to abdominal pain in preclinical models of IBD, and TRP melastatin 3 (TRPM3) contributes to inflammatory joint and bladder pain. This is the first study to assess TRPM3’s role in IBD-associated pain. I utilized immunohistochemistry, Ca2+ imaging, and afferent nerve recording to evaluate TRPM3 protein expression in colon-projecting dorsal root ganglion (DRG) neurons and colonic nerve terminals, as well as functional activity at the neuronal and nerve levels. TRPM3 protein expression was observed in 76.1 % of colon-projecting DRG neurons and TRPM3 was also present in putative axons within the mouse colon. TRPM3 was functionally expressed in 62-70 % of T13-L5 DRG neurons from healthy mice depending on the agonist used. The TRPM3 inhibitor isosakuranetin suppressed CIM-0216 and pregnenolone sulphate sodium (PSS)-induced increases in intracellular Ca2+. The magnitude of CIM-0216 and PSS-induced increases in intracellular Ca2+ were significantly greater in neurons from mice with colitis compared to healthy mice. Additionally, the percentage of DRG neurons from mice with colitis responding to CIM-0216 was significantly increased. In afferent nerve experiments, CIM-0216 increased the mean firing frequency of colonic afferent nerves from healthy mice and mice with colitis. Isosakuranetin inhibited the mechanosensitive response to distension of wide-dynamic range afferent nerve units from mice with colitis but had no effect in healthy mice. Therefore, TRPM3 protein is expressed in colon-projecting DRG neurons and functionally expressed in colonic afferent nerves. TRPM3 is also sensitized during colitis and selectively contributes to mechanosensation of wide-dynamic range colonic afferent nerve units during colitis. This study furthers our understanding of the mechanosensitive ion channels that contribute to visceral sensation and elucidates TRPM3 as a potential target for IBD-associated pain.
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