A prominent signaling pathway in the development of
neuropathic pain involves
ATP acting on microglial
purinergic receptors. Among the P2Y metabotropic receptors, we reported before that the P2Y12 receptor is upregulated in microglia following nerve injury and involved in the phosphorylation of
p38 MAPK, and in the development of
pain behavior. In this study, we examined the expression of P2Y6, P2Y13, and P2Y14 receptors in the spinal cord and whether these receptors are involved in the pathogenesis of
neuropathic pain following
peripheral nerve injury. We found that spared nerve injury induced a dramatic increase of not only P2Y12, but also P2Y6, 13, and 14 receptor
mRNA expression in spinal microglia. The increase continued for at least 2 weeks after injury. To determine whether
p38 MAPK can induce the expression of P2Y receptors, we administered intrathecally the
p38 MAPK inhibitor
SB203580 and found that it significantly suppressed P2Y6, P2Y13, and P2Y14 but not P2Y12 mRNAs.
Intrathecal injection of the specific P2Y6 antagonist
MRS2578, specific P2Y13 antagonist
MRS2211 or P2Y14 antisense LNA, attenuated mechanical
pain hypersensitivity. The mixture of three antagonists for P2Y6, 12, and 13 showed a longer suppressive effect on
pain behavior than the individual treatments. Our data demonstrate that
ATP and other
nucleotides may stimulate activated microglia with the upregulation of P2Y6, P2Y12, P2Y13, and P2Y14 receptors following nerve injury and these receptors are involved in the development of
neuropathic pain.