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 Ca(2+)/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)-N-methylbenzylamine) (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.
Chen
Yan
Y
Department of Biopharmaceutical Sciences, University of Illinois, Chicago, Illinois 60612, USA.
Luo
Fang
F
Yang
Cheng
C
Kirkmire
Chelsea M
CM
Wang
Zaijie Jim
ZJ
D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides