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

Abstract

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 1st to 3rd week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2nd to 3rd week. Western blot analysis revealed that elevated p-CaMKIIα levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKIIα levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKIIα immune positive DRG neurons (stained with NeuN) in the 2nd and 3rd week and p-CaMKIIα 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-CaMKIIα and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKIIα upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKIIα may be an effective pharmacological target for DNP management.

Electroacupuncture Alleviates Diabetic Neuropathic Pain and Downregulates p‐PKC and TRPV1 in Dorsal Root Ganglions and Spinal Cord Dorsal Horn

“…In this study, FBG increased and BW decreased remarkably starting at 1 week after STZ injection. PWL decreased remarkably starting at 2 weeks after STZ injection, indicating the successful establishment of the DNP model, which consisted with our previous research [29].…”

Unveiling Potential Therapies: Molecular Docking Analysis of CAMKK2 and Its Mutant Variants with CAMKK2 Inhibitors in Indonesian Patients with HIV-Sensory Neuropathy

“…Administration of intraplantar KN-93 injection at minimum of 50 nmol relieved DNP and downregulated p-CAMKII ɑ and P2X3 levels. 21 As it was discussed before, CAMKII plays a role in modulating nociceptive pain, where 50% of DRG rat neurons expressed CAMKII. The increase in calcium currents from internal storage have been observed in peripheral sensory neurons and DRG.…”

Electroacupuncture alleviates streptozotocin-induced diabetic neuropathic pain via suppressing phosphorylated CaMKIIα in rats

“…Studies have shown that STZ injection can successfully establish a DNP model, so this model was used in this experiment to investigate the mechanism of EA to alleviate DNP. Our previous studies have found that the upregulation of p-CaMKIIα in DNP rats’ DRG may be an underlying mechanism of the development of DNP [ 46 ]. According to the experimental results, it was found that the expressions of p-CaMKIIα of DNP model group rats had increased in both SCDH and DRG compared to the normal group, while CaMKIIα had no statistical differences.…”