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Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II.

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.
AuthorsFang Luo, Cheng Yang, Yan Chen, Pradeep Shukla, Lei Tang, Lili X Wang, Zaijie Jim Wang
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 325 Issue 1 Pg. 267-75 (Apr 2008) ISSN: 1521-0103 [Electronic] United States
PMID18178903 (Publication Type: Journal Article)
Chemical References
  • Benzylamines
  • Sulfonamides
  • KN 93
  • Freund's Adjuvant
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
Topics
  • Animals
  • Benzylamines (administration & dosage, pharmacology)
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors)
  • Dose-Response Relationship, Drug
  • Freund's Adjuvant
  • Hyperalgesia (drug therapy)
  • Inflammation (chemically induced, drug therapy, pathology)
  • Mice
  • Mice, Inbred ICR
  • Pain (chemically induced, drug therapy)
  • Remission Induction
  • Spine
  • Sulfonamides (administration & dosage, pharmacology)

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