Abstract
Ca2+/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.
Footnotes
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F.L. and C.Y. contribute equally to the work.
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F.L. is a visiting fellow from the Department of Anesthesiology, Tongji Medical College, Wuhan, China.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132167.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; CaMKII, Ca2+/calmodulin-dependent protein kinase II; pCaMKII, phosphorylated CaMKII; CFA, complete Freund's adjuvant; CCI, chronic constriction injury; KN93, [2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine); KN92, 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; i.pl. intarplantarly.
- Received September 28, 2007.
- Accepted January 3, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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