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Anesth Analg 2008; 106:978-984
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318163f71b
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PAIN MECHANISMS

The Interaction Between Inhibitors of Nitric Oxide Synthase and Cyclooxygenase in Formalin-Induced Pain in Mice: An Isobolographic Study

Abdul-Shakoor Bhat, PhD, Surendra Kumar Tandan, PhD, Dinesh Kumar, PhD, Vamsi Krishna, PhD, and Vellanki Ravi Prakash, PhD

From the Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.

Address correspondence and reprint requests to S.K. Tandan, PhD, Principal Scientist, Division of Pharmacology & Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, UP 243 122, India. Address e-mail to sktandan{at}ivri.up.nic.in.

Abstract

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.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2008 by the International Anesthesia Research Society.