Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain
Résumé
Background Activation of proteinase-activated receptor-
4 (PAR-4) from the colonic lumen has an antinociceptive
effect to colorectal distension (CRD) in mice
in basal conditions. We aimed to determine the
functional localization of the responsible receptors
and to test their role in two different hyperalgesia
models. Methods Mice received PAR-4 activating
peptide (PAR-4-AP, AYPGKF-NH2) or vehicle intraperitoneally
(IP), and abdominal EMG response to
CRD 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 role
of lymphocytes in the antihyperalgesic effect. The
effects 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 sulfonic
acid (TNBS) colitis. Spinal Fos protein expression was
visualized by immunohistochemistry. Key Results The
antinociceptive effect of PAR-4-AP disappeared when
was administrered IP, or with the blockade of colonic
epithelial tight junctions, suggesting that PAR-4-AP
needs to reach directly the nerve terminals in the colon.
The CRD-induced spinal Fos overexpression was
reduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesic
in both hyperalgesia models and in mice
with impaired lymphocytes. The PAR-4-antagonist
significantly increased the TNBS, but not the WAS-induced
colonic hyperalgesia. Conclusions & Inferences
The antinociceptive effect of PAR-4-AP depends
on its penetration to the colonic mucosa. The PAR-4
activation is endogenously involved as a feedback loop
to attenuate inflammatory colonic hyperalgesia to
CRD.
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