We have previously shown that endogenous
adenosine 5'-triphosphate (
ATP), via P2X3 and P2X2/3 receptors, plays an essential role in
carrageenan-induced articular
hyperalgesia model in rats' knee joint. In the present study, we used the rat knee joint incapacitation test,
Enzyme-Linked
Immunosorbent Assay (ELISA), and
myeloperoxidase enzyme activity assay, to test the hypothesis that the activation of P2X3 and P2X2/3 receptors by their agonist induces articular
hyperalgesia mediated by the inflammatory mediators
bradykinin,
prostaglandin,
sympathomimetic amines, pro-inflammatory
cytokines and by neutrophil migration. We also tested the hypothesis that the activation of P2X3 and P2X2/3 receptors contributes to the articular
hyperalgesia induced by the inflammatory mediators belonging to
carrageenan inflammatory cascade. The non-selective P2X3 and P2X2/3 receptors agonist αβ-meATP induced a dose-dependent articular
hyperalgesia, which was significantly reduced by the selective antagonists for P2X3 and P2X2/3 receptors (A-317491),
bradykinin B1- (DALBK) or B2-receptors (
bradyzide), β1-(atenolol) or β2-adrenoceptors (ICI-118,551), by the pre-treatment with
cyclooxygenase inhibitor (
indomethacin) or with the nonspecific
selectin inhibitor (
Fucoidan). αβ-meATP induced the release of pro-inflammatory
cytokines TNFα, IL-1β,
IL-6, and CINC-1, as well as the neutrophil migration. Moreover, the co-administration of
A-317491 significantly reduced the articular
hyperalgesia induced by
bradykinin,
prostaglandin E2 (
PGE2), and
dopamine. These findings suggest that peripheral P2X3 and P2X2/3 receptors activation induces articular
hyperalgesia by an indirect sensitization of the primary afferent nociceptor of rats' knee joint through the release of inflammatory mediators. Further, they also indicate that the activation of these
purinergic receptors by endogenous
ATP mediates the
bradykinin-, PGE2-, and
dopamine-induced articular
hyperalgesia.