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Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain
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Background Activation of proteinase-activated receptor-4 (PAR-4) from the colonic lumen has an antinociceptiveeffect to colorectal distension (CRD) in micein basal conditions. We aimed to determine thefunctional localization of the responsible receptorsand to test their role in two different hyperalgesiamodels. Methods Mice received PAR-4 activatingpeptide (PAR-4-AP, AYPGKF-NH2) or vehicle intraperitoneally(IP), and abdominal EMG response toCRD was measured. The next group received PAR-4-AP intracolonically (IC) with or without 2,4,6-triaminopyrimidine,a chemical tight junction blocker,before CRD. The SCID mice were used to test the roleof lymphocytes in the antihyperalgesic effect. Theeffects of PAR-4-AP and PAR-4-antagonist (P4pal-10)were evaluated in water avoidance stress (WAS)model and low grade 2,4,6-trinitrobenzene sulfonicacid (TNBS) colitis. Spinal Fos protein expression wasvisualized by immunohistochemistry. Key Results Theantinociceptive effect of PAR-4-AP disappeared whenwas administrered IP, or with the blockade of colonicepithelial tight junctions, suggesting that PAR-4-APneeds to reach directly the nerve terminals in the colon.The CRD-induced spinal Fos overexpression wasreduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesicin both hyperalgesia models and in micewith impaired lymphocytes. The PAR-4-antagonistsignificantly increased the TNBS, but not the WAS-inducedcolonic hyperalgesia. Conclusions & InferencesThe antinociceptive effect of PAR-4-AP dependson its penetration to the colonic mucosa. The PAR-4activation is endogenously involved as a feedback loopto attenuate inflammatory colonic hyperalgesia toCRD.
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