Abstract
We have found that mutation of d-amino acid oxidase (DAO) diminished formalin-induced tonic pain. The present research further studied the analgesic effects of a series of DAO inhibitors in this model. 5-Chlorobenzo[d]isoxazol-3-ol (CBIO), 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (compound 8), 5-methylpyrazole-3-carboxylic acid (AS057278), sodium benzoate, and 4-nitro-3-pyrazole carboxylic acid (NPCA) inhibited rat spinal cord-derived DAO activity in a concentration-dependent manner, with maximal inhibition of 100% and potency rank of CBIO > compound 8 > AS057278 > sodium benzoate > NPCA. In rats, intrathecal injections of CBIO, compound 8, AS057278, and sodium benzoate but not NPCA specifically prevented formalin-induced tonic pain but not acute nociception, with the same potency order as in the DAO activity assay. The highly potent analgesia of DAO inhibitors was evidenced by CBIO, which prevented 50% pain at 0.06 μg, approximately 5-fold the potency of morphine. CBIO given after formalin challenge also reversed the established pain state to the same degree as prevention. The antihyperalgesic potencies of these DAO inhibitors were highly correlated to their inhibitions of spinal DAO activity. Maximum inhibition of pain by these compounds was approximately 60%, comparable with that of the N-methyl-d-aspartic acid receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), suggesting that a larger portion of formalin-induced tonic pain is “DAO-sensitive,” whereas the remaining 40% of tonic pain and acute nociception is “DAO-insensitive.” These findings, combined with our previous DAO gene mutation and induction results, indicate spinal DAO mediates both induction and maintenance of formalin-induced tonic pain and further validate spinal DAO as a novel and efficacious target molecule for the treatment of chronic pain.
Footnotes
This study was supported by the National Natural Science Foundation of China [Grants 81072623, 30973581]; the Mega New Drug Development Program of China [Grant 2009ZX09301-007]; and a Shanghai Jiao Tong University School of Pharmacy Predoctoral Fellowship (to N.G.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.172353.
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ABBREVIATIONS:
- DAO
- d-amino acid oxidase
- rsDAO
- rat spinal cord-derived DAO
- pkDAO
- porcine kidney-derived DAO
- NMDA
- N-methyl-d-aspartic acid
- CBIO
- 5-chlorobenzo[d]isoxazol-3-ol
- compound 8 (sc-203909)
- 4H-thieno[3,2-b]pyrrole-5-carboxylic acid
- compound 2
- 3-hydroxyquinolin-2-(1H)-one
- AS057278
- 5-methylpyrazole-3-carboxylic acid
- NPCA
- 4-nitro-3-pyrazole carboxylic acid
- MK-801
- (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- DMSO
- dimethyl sulfoxide
- ANOVA
- analysis of variance
- AUC
- area under the curve
- Emax
- maximum effect.
- Received July 6, 2010.
- Accepted October 14, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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