Activation of cytosolic phospholipase A(2 )in dorsal root ganglion neurons by Ca(2+)/calmodulin-dependent protein kinase II after peripheral nerve injury

BACKGROUND: Peripheral nerve injury leads to a persistent neuropathic pain state in which innocuous stimulation elicits pain behavior (tactile allodynia), but the underlying mechanisms have remained largely unknown. We have previously shown that spinal nerve injury induces the activation of cytosolic phospholipase A(2 )(cPLA(2)) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia. However, little is known about the signaling pathway that activates cPLA(2 )after nerve injury. In the present study, we sought to determine the mechanisms underlying cPLA(2 )activation in injured DRG neurons in an animal model of neuropathic pain, focusing on mitogen-activated protein kinases (MAPKs) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). RESULTS: Pharmacological inhibition of either p38 or extracellular signal-regulated kinase (ERK) in the injured DRG, which led to suppression of the development of tactile allodynia, did not affect cPLA(2 )phosphorylation and translocation after nerve injury. By contrast, a CaMKII inhibitor prevented the development and expression of nerve injury-induced tactile allodynia and reduced both the level of cPLA(2 )phosphorylation and the number of DRG neurons showing translocated cPLA(2 )in response to nerve injury. Applying ATP to cultured DRG neurons increased the level of both phosphorylated cPLA(2 )and CaMKII in the vicinity of the plasma membrane and caused physical association of these two proteins. In addition, ATP-stimulated cPLA(2 )and CaMKII phosphorylation were inhibited by both a selective P2X(3)R/P2X(2+3)R antagonist and a nonselective voltage-dependent Ca(2+ )channel (VDCC) blocker. CONCLUSION: These results suggest that CaMKII, but not MAPKs, has an important role in cPLA(2 )activation following peripheral nerve injury, probably through P2X(3)R/P2X(2+3)R and VDCCs in primary afferent neurons.