Inhibition of phosphorylated calcium/calmodulin-dependent protein kinase IIα relieves streptozotocin-induced diabetic neuropathic pain through regulation of P2X3 receptor in dorsal root ganglia

Diabetic neuropathic pain (DNP) is frequent among patients with diabetes. We previously showed that P2X3 upregulation in dorsal root ganglia (DRG) plays a role in streptozotocin (STZ)-induced DNP but the underlying mechanism is unclear. Here, a rat model of DNP was established by a single injection of STZ (65 mg/kg). Fasting blood glucose was significantly elevated from the 1(st) to 3(rd) week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2(nd) to 3(rd) week. Western blot analysis revealed that elevated p-CaMKII alpha levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKII alpha levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKII alpha immune positive DRG neurons (stained with NeuN) in the 2(nd) and 3(rd) week and p-CaMKII alpha was co-expressed with P2X3 in DNP rats. KN93, a CaMKII antagonist, significantly reduce mechanical hyperalgesia and thermal hyperalgesia and these effects varied dose-dependently, and suppressed p-CaMKII alpha and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKII alpha upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKII alpha may be an effective pharmacological target for DNP management.