Reversal of chronic inflammatory pain by acute inhibition of Ca 2+ /calmodulin-dependent protein kinase II

Fang Luo, Cheng Yang, Yan Chen, Pradeep Kumar Shukla, Lei Tang, Lili X. Wang, Jim Wang Zaijie

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume325
Issue number1
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Hyperalgesia
Chronic Pain
Freund's Adjuvant
Trifluoperazine
Protein Kinase Inhibitors
Inhibition (Psychology)
Pain
Ion Channels
Protein Kinases
Antipsychotic Agents
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Reversal of chronic inflammatory pain by acute inhibition of Ca 2+ /calmodulin-dependent protein kinase II . / Luo, Fang; Yang, Cheng; Chen, Yan; Shukla, Pradeep Kumar; Tang, Lei; Wang, Lili X.; Zaijie, Jim Wang.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 325, No. 1, 01.04.2008, p. 267-275.

Research output: Contribution to journalArticle

Luo, Fang ; Yang, Cheng ; Chen, Yan ; Shukla, Pradeep Kumar ; Tang, Lei ; Wang, Lili X. ; Zaijie, Jim Wang. / Reversal of chronic inflammatory pain by acute inhibition of Ca 2+ /calmodulin-dependent protein kinase II In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 325, No. 1. pp. 267-275.
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