Acute Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

The limited data that currently exist for the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in neuropathic pain are conflicting. In the present study, we tested the hypothesis that CaMKII is required for the maintenance of neuropathic pain in a rodent model of experimental mononeuropathy. Spinal nerve L-5/L-6 ligation (SNL) was found to increase the spinal activity of CaMKII (pCaMKII) on the ipsilateral (but not contralateral) side. This effect was blocked by 2-[N-(2-hydroxyethyl)-N( 4-methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)--Nmethylbenzylamine) (KN93) (intrathecal injection), a CaMKII inhibitor. Acute treatment with KN93 dose-dependently reversed SNL-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 lasted for at least 2 to 4 h. 2-[N( 4-Methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN92) (45 nmol i.t.), an inactive analog of KN93, showed no effect on SNL-induced CaMKII activation, allodynia, or hyperalgesia. We further examined the pharmacologic action of trifluoperazine, a clinically used antipsychotic drug that we found to be a potent CaMKII inhibitor in these assays. Trifluoperazine (administered intraperitoneally or by mouth) dose-dependently reversed SNL-induced mechanical allodynia, thermal hyperalgesia, and CaMKII activation without causing locomotor impairment in mice at the highest doses used. In conclusion, our findings support a critical role of CaMKII in neuropathic pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of neuropathic pain.