P2X7 receptors play an important role in inflammatory
hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that
P2X7 receptor activation induces
mechanical hyperalgesia via the inflammatory mediators
bradykinin,
sympathomimetic amines,
prostaglandin E2 (
PGE2), and pro-inflammatory
cytokines and via neutrophil migration in rats. We found that 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium
salt (
BzATP), the most potent
P2X7 receptor agonist available, induced a dose-dependent
mechanical hyperalgesia that was blocked by the
P2X7 receptor-selective antagonist
A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist
TNP-ATP. These findings confirm that, although
BzATP also acts at both P2X1 and P2X3 receptors,
BzATP-induced
hyperalgesia was mediated only by
P2X7 receptor activation. Co-administration of selective antagonists of
bradykinin B1 (Des-Arg(8)-Leu(9)-BK (DALBK)) or B2 receptors (
bradyzide), β1 (
atenolol) or β2
adrenoceptors (
ICI 118,551), or local pre-treatment with the
cyclooxygenase inhibitor indomethacin or the nonspecific
selectin inhibitor
fucoidan each significantly reduced
BzATP-induced
mechanical hyperalgesia in the rat hind paw.
BzATP also induced the release of the pro-inflammatory
cytokines tumor necrosis factor α (TNF-α),
interleukin (IL)-1β,
IL-6 and
cytokine-induced neutrophil chemoattractant-1 (CINC-1), an effect that was significantly reduced by
A-438079. Co-administration of DALBK or
bradyzide with
BzATP significantly reduced
BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral
P2X7 receptor activation induces
mechanical hyperalgesia via inflammatory mediators, especially
bradykinin, which may contribute to pro-inflammatory
cytokine release. These pro-inflammatory
cytokines in turn may mediate the contributions of
PGE2,
sympathomimetic amines and neutrophil migration to the
mechanical hyperalgesia induced by local
P2X7 receptor activation.