Objective Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.
Design The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS.
Results RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3–30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS.
Conclusions Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.
- abdominal pain
- ION channels
- irritable bowel syndrome
- visceral hypersensitivity
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EP and JA-L contributed equally.
Contributors EP, MVF, MW and GB planned and designed the experiments. BDW, NH, JGDM and MB planned and designed the experiments in the post-TNBS colitis model. EP, JA-L and PJ performed and analysed the Ca2+ experiments in DRG neurons and rectal biopsies experiments. MVF carried out the in vivo animal protocol and analysed visceromotor responses and compliance. MVF and JA-L performed and analysed colonic permeability assessments. NH and JGDM performed and analysed the experiments in the post-TNBS colitis model. SAT and JA-L performed the staining in retrograde labelled DRG neurons. PVB, YAA and KT provided technical expertise. EP, MVF, JA-L and GB wrote and revised the manuscript. All other authors corrected and approved the final version of the manuscript.
Funding This work was supported by the Research Foundation—Flanders (FWO-SBO grant nr. S001017). MVF, MMW, PJ, JA-L and YAA were supported by an FWO doctoral or postdoctoral fellowship (1110017N/1110019N, 1248513N, 12R5219N, 12X9820N and 12H8217N). EP was supported by an Early Stage Researcher Marie Curie fellowship (NeuroGUT).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All participants gave informed consent and Leuven University Hospital Human Ethics Committee approved the protocol (ethical approval number ML9438 and S55484).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All the relevant data generated and analysed during the current study are available upon reasonable request to the corresponding author.
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