Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major protein kinase that is capable of regulating the activities of many ion channels and receptors. In the present study, the role of CaMKII in the complete Freund's adjuvant (CFA)-induced inflammatory pain was investigated. Intraplantarly injected CFA was found to induce spinal activity of CaMKII (phosphorylated CaMKII), which was blocked by KN93 [[2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)], a CaMKII inhibitor. Pretreatment with KN93 (i.t.) dose-dependently prevented the development of CFA-induced thermal hyperalgesia and mechanical allodynia. Acute treatment with KN93 (i.t.) also dose-dependently reversed CFA-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 started in 30 min and lasted for at least 2 to 4 h. KN92 (45 nmol i.t.) [2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine], an inactive analog of KN93, showed no effect on CFA-induced CaMKII activation, allodynia, or hyperalgesia. Furthermore, our previous studies identified trifluoperazine, a clinically used antipsychotic drug, to be a potent CaMKII inhibitor. Inhibition of CaMKII activity by trifluoperazine was confirmed in the study. In addition, trifluoperazine (i.p.) dose-dependently reversed CFA-induced mechanical allodynia and thermal hyperalgesia. The drug was also effectively when given orally. In conclusion, our findings support a critical role of CaMKII in inflammatory pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of chronic pain.
Luo
Fang
F
Department of Biopharmaceutical Sciences, University of Illinois, 833 South Woods Street, Chicago, IL 60612, USA.
Yang
Cheng
C
Chen
Yan
Y
Shukla
Pradeep
P
Tang
Lei
L
Wang
Lili X
LX
Wang
Zaijie Jim
ZJ
D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D012074:Remission Induction; D013131:Spine; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005620:Freund's Adjuvant; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides