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.
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Authors | Fang Luo, Cheng Yang, Yan Chen, Pradeep Shukla, Lei Tang, Lili X Wang, Zaijie Jim Wang |
Journal | The 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 |
PMID | 18178903
(Publication Type: Journal Article)
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Chemical References |
- Benzylamines
- Sulfonamides
- KN 93
- Freund's Adjuvant
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
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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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