Document Detail

The interaction between inhibitors of nitric oxide synthase and cyclooxygenase in formalin-induced pain in mice: an isobolographic study.
MedLine Citation:
PMID:  18292449     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: An interaction between nitric oxide (NO) and cyclooxygenases (COX) in the production of prostaglandins in carrageenan-induced inflammation has been established. However, limited information is available about the interaction between inducible NO synthase (iNOS) and COX inhibitors in pain perception. Therefore, in the present study we assessed the nature of the interaction between S-methylisothiourea (a moderately selective iNOS inhibitor) with rofecoxib (selective COX-2 inhibitor) and mefenamic acid (a nonselective COX inhibitor) in formalin- induced pain in mice. METHODS: The dose-response relation of S-methylisothiourea, rofecoxib, mefenamic acid, and their combination was studied in the late phase of formalin-induced pain in mice over the time spent in licking the hindpaw after formalin injection. The interaction was evaluated by simultaneous administration of fixed proportions of S-methylisothiourea with each COX inhibitor and the nature of the interaction was determined by isobolographic analysis. RESULTS: Each drug alone produced a dose-dependent suppression of the late stage of formalin-induced behaviors with rank order of potency being rofecoxib > mefenamic acid > S-methylisothiourea. Isobolographic analysis of the combination of S-methylisothiourea with rofecoxib or mefenamic acid revealed a synergistic interaction. The experimental ED50 of the combination was significantly lower than the theoretical additive ED50 of the corresponding drug combination that substantiated the synergistic interaction between iNOS or NO and COX isoforms. CONCLUSIONS: Our results explicitly indicate the synergistic nature of the interaction between NOS and COX inhibitors in formalin-induced nociceptive behavior in mice, and provide an alternative approach for controlling pain.
Abdul-Shakoor Bhat; Surendra Kumar Tandan; Dinesh Kumar; Vamsi Krishna; Vellanki Ravi Prakash
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Anesthesia and analgesia     Volume:  106     ISSN:  1526-7598     ISO Abbreviation:  Anesth. Analg.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-02-22     Completed Date:  2008-03-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1310650     Medline TA:  Anesth Analg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  978-84, table of contents     Citation Subset:  AIM; IM    
Division of Pharmacology & Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP 243 122, India.
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MeSH Terms
Behavior, Animal / drug effects*
Cyclooxygenase 1 / metabolism*
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / pharmacology*,  therapeutic use
Cyclooxygenase Inhibitors / pharmacology*,  therapeutic use
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Drug Therapy, Combination
Enzyme Inhibitors / pharmacology*,  therapeutic use
Isothiuronium / analogs & derivatives,  pharmacology
Lactones / pharmacology
Mefenamic Acid / pharmacology
Membrane Proteins / metabolism*
Nitric Oxide Synthase Type II / antagonists & inhibitors*,  metabolism
Pain / chemically induced,  enzymology,  prevention & control*
Pain Measurement
Sulfones / pharmacology
Time Factors
Reg. No./Substance:
0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Enzyme Inhibitors; 0/Lactones; 0/Membrane Proteins; 0/Sulfones; 0/rofecoxib; 22584-04-9/Isothiuronium; 2986-19-8/S-methylisothiopseudouronium; 50-00-0/Formaldehyde; 61-68-7/Mefenamic Acid; EC Oxide Synthase Type II; EC protein, mouse; EC 1.14.99.-/Ptgs2 protein, mouse; EC 1; EC 2; EC protein, mouse

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