Research ArticlePain

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

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Sci. Signal.  18 Dec 2018:
Vol. 11, Issue 561, eaal2171
DOI: 10.1126/scisignal.aal2171

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Inducing pain in IBS

A symptom of irritable bowel syndrome (IBS) that accompanies altered bowel function is abdominal pain. Noting that various polyunsaturated fatty acids (PUFAs) are implicated in modulating inflammation in patients with IBS, Bautzova et al. found that the abundance of the PUFA 5-oxoETE was selectively increased in colonic biopsies from patients with a subtype of IBS characterized by constipation (IBS-C). 5-oxoETE increased pain sensitivity in mice without eliciting inflammation and stimulated both mouse and human dorsal root ganglia neurons expressing the GPCR Mrgprd. Knockdown of Mrgprd in mice reduced the percentage of neurons that responded to 5-oxoETE and decreased pain sensitivity, suggesting that this PUFA may mediate abdominal pain in patients with IBS-C.

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 patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic 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 ganglion (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.

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