5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein–coupled receptor D

Abstract

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in IBS patients and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxo-eicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca2+-imaging of dorsal root ganglia (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)– and pertussis toxin–dependent mechanism, suggesting that the effect was mediated by a G protein–coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

“…Moreover, our findings imply that Mrgprc11 might play an important role in visceral hypersensitivity underlying chronic abdominal pain disorders. Bautzova and colleagues recently provided evidence that Mrgprd plays a pivotal role in abdominal pain in constipation‐predominant IBS . Their findings, together with the newly established role for Mrgprc11 in the present study, identify Mrgprs in general as novel targets for chronic abdominal pain research.…”

“…The results of our tracing studies, however, unambiguously indicate that both at the mRNA and protein level, Mrgprc11 is present in the somata of DRG neurons that innervate the colon. Recently, the expression of another Mrgpr member, Mrgprd, was revealed in mouse splanchnic colonic DRG neurons . Mrgprd expression was predominantly found in non‐peptidergic, IB4‐positive DRG neurons, whereas our results show that Mrgprc11 is mainly expressed in DRG neurons co‐expressing the peptidergic marker CGRP.…”

Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity

“…We identify mechanisms by which MrgprA3, MrgprC11, and the bile acid receptor TGR5 contribute to the induction of visceral hypersensitivity and altered behavior in response to known pruritogens. Our findings add to the recent discovery of an endogenous mediator, 5-Oxo-eicosatetraenoic acid (5-oxoETE), which activates afferents via a related MRGPR, MRGPRD, to evoke visceral hypersensitivity (55). Our findings demonstrate that the roles of TGR5, MrgprA3, and MRGPRC11 extend beyond itch sensation in the skin, adding to recent work demonstrating that MrgprC11 expressed on vagal sensory neurons contributes to bronchoconstriction and airway hyperresponsiveness (56).…”

Evoked and spontaneous pain assessment during tooth pulp injury

“…Bacteria most highly associated with cold and heat sensitive irreversible pulpitis infections are actually gram positive 46 , and may influence pulp nociceptors by different mechanisms than LPS-mediated activation of TLR4 or other TLRs. Other bacterial products 47 or aspects of inflammation, such as oxidative stress may also recruit both TRP channel expressing nociceptors 48 and Mrgprd 49 . Clearly, more work is needed on our path to improving the care of endodontic patients.…”