Effect of Celecoxib on the Peripheral NO Production

Document Type: Original Article

Author

Department of Pharmacology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

Abstract

Objective(s)
Celecoxib acts through both COX-2-dependent and -independent pathways. According to the paradoxical effect of NO on the inflammatory and nociceptive signal processing, the present study designed to evaluate the probable contribution of NO in the analgesic and anti-inflammatory properties of celecoxib.
Materials and Methods
Different intensities of inflammatory pain were induced by acute and chronic sc administration of 1%, 2.5%, or 5% formalin and spectrophotometrical analysis of the serum nitrite was performed. Then, in the pretreatment process, the effect of celecoxib (10, 20, or 40 mg/kg/ip) was evaluated on the inflammatory pain induced-nitrite. Also, the effect of celecoxib alone (under non-inflammatory condition) was evaluated on the peripheral NO production and the results compared with that of the vehicle.
Results
Formalin-induced inflammatory pain led to an enhancement of the serum nitrite in intensity- and time- dependent manners. Celecoxib (40 mg/kg/ip), except its ineffectiveness on the nitrite level, induced 1.5 hr after 5% formalin, reduced production of formalin-induced nitrite in other cases. Meanwhile, under non‌inflammatory condition, 1.5 hr after the administration of celecoxib (40 mg/kg/ip), a considerable elevation of nitrite was observed. Celecoxib 10 or 20 mg/kg/ip did not show a significant effect on either inhibition or stimulation of the peripheral NO.
Conclusion
NO is involved both in the inflammatory and non-inflammatory conditions. It seems that celecoxib exerts a dual effect on the peripheral NO production; it prevents overproduction of NO due to the induction of inflammatory pain, while, it stimulates NO synthesis at the early stage of its action.

Keywords


1.De Witt DL. Cox-2-selective inhibitors: The new super aspirins. Mol Pharm 1999; 55:625-631. 

2.Frampton JE, Keating GM. Celecoxib: A review of its use in the management of arthritis and acute pain. Drugs 2007; 67:2433-2472.

3.Acco A, Alves da Silva MH, Batista MR, Yamamoto NS, Bracht A. Action of celecoxib on hepatic metabolic changes induced by the Walker-256 tumour in rats. Basic Clin Pharmacol Toxicol 2007; 101:294-300.

4.Ferrario A, Fisher AM, Rucker N, Gomer CJ. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors. Cancer Res 2005; 65: 9473-9478.

5.Connail R, McCrory MD, Sten MD. Cyclooxygenase inhibition for postoperative analgesia. Anesth Analg 2002; 95: 169-176.

6.Anbar M, Gratt BM. Role of nitric oxide in the physiopathology of pain. J Pain Symptom Manage 1997; 14: 225-254.

7.Tang Q, Svensson CI, Fitzsimmons B, Webb M, Yaksh TL, Hua XY. Inhibition of spinal constitutive NOS-2 by 1400 W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation. Eur J Neurosci 2007; 25:2964-2972.

8.Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43:109-114.

9.Benamar K, Geller EB, Adler MW. Role of the nitric oxide pathway in kappa-opioid-induced hypothermia in rats. J Pharmacol Exp Ther 2002; 303:375-378.

10.Homayoun H, Khavandgar S, Dehpour AR. The selective role of nitric oxide in opioid-mediated footshock stress antinociception in mice. Physiol Behav 2003; 79:567-573.

11.Patil CS, Jain NK, Singh VP, Kulkarni SK. Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception. Indian J Exp Biol 2004; 42: 361-367.

12.Przesmycki K, Dzieciuch JA, Czuczwar SJ, Kleinrok Z. Nitric oxide modulates spinal antinociceptive effect of clonidine but not that of baclofen in the formalin test in rats. Eur Neuropsychopharmacol 1999; 9:115-121.

13.Chen SR, Khan GM, Pan HL. Antiallodynic effect of intrathecal neostigmine is mediated by spinal nitric oxide in a rat model of diabetic neuropathic pain. Anesthesiology 2001; 95:1007-1012.

14.Rocha JC, Ribeiro RA, Peixoto MEB, de Q Cunha SJF, da Rocha FAC. Dual effect of nitric oxide in articular inflammatory pain in zymosan-induced arthritis in rats. Br J Pharmacol 2002; 136:588-596.

15.Arasapam G, Scherer M, Cool JC, Foster BK, Xian CJ. Roles of COX-2 and iNOS in the bony repair of the injured growth plate cartilage. J Cell Biochem 2006; 99:450-461.

16.Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain. Proc Natl Acad Sci USA 2002; 91:2013-12017.

17.Ahmadiani A, Hosseiny J, Semnanian S, Javan M, Saeedi F, Kamalinejad M, et al. Antinociceptive and anti-inflammatory effects of Elaeagnus angustifolia fruit extract. J Ethnopharmacol 2000; 72:287-292.

18.Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 1982; 126:131-138.

19.Connail R, McCrory MD, Sten GE, Clancy R, Varenika B, Huang W, Ballou L, Attur M, Amin AR, Abramson SB. Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J Immunol 2000; 165: 1582-1587.

20.Ozgocmen S, Ardicoglu O, Erdogan H, Fadillioglu E, Gudul H. In vivo effect of celecoxib and tenoxicam on oxidant/anti-oxidant status of patients with knee osteoarthritis. Ann Clin Lab Sci 2005; 35:137-143.

21.Matsuda K, Nakamura S, Matsushita T. Celecoxib inhibits nitric oxide production in chondrocytes of ligament- damaged osteoarthritic rat joints. Rheumatol Int 2006; 26: 991-995.

22.Shinmura K, Xuan YT, Tang XL, Kodani E, Han H, Zhu Y, Bolli R. Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res 2002; 90:602-612.

23.Ryu YS, Lee JH, Seok JH, Hong JH, Lee YS, Lim JH, et al. Acetaminophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regulation of NF-kappaB by acetaminophen and salicylates. Biochem Biophys Res Commun 2000; 272: 758-764.

24.Shinmura K,Tang XL, Wang Y, Xuan YT, Liu SQ, Takano H, et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci USA 2000; 97:10197-10202.

25.Bertolini A, Ottani A. Dual acting anti-inflammatory drugs: a reappraisal. Pharmacol Res 2001; 44:437-450.

26.Gladwin MT, Raat NJH, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, et al. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 2006; 291:H2026-H2035.

27.Shiu HP, Most D, Efron DT, Witte MB, Barbul A. Supplemental L-arginine enhances wound healing in diabetic rats. Wound Repair Regen 2003; 11:198-203. 

28.Petrofsky J, Hinds CM, Batt J, Prowse M, Suh HJ. The interrelationships between electrical stimulation, the environment surrounding the vascular endothelial cells of the skin, and the role of nitric oxide in mediating the blood flow response to electrical stimulation. Med Sci Monit 2007; 13:391-397.

29.Guirguis MS, Sattari S, Jamali F. Pharmacokinetics of celecoxib in the presence and absence of interferon-induced acute inflammation in the rat: Application of a novel HPLC assay. J Pharm Pharmaceut Sci 2001; 4:1-6.

30.Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger. Neuron 1992; 8:3-11.

31.Coleman JW. Nitric oxide in immunity and inflammation. Int Immunopharmacol 2001; 1:1397-1406.

32.Klein T, Eltze M, Grebe T, Hatzelmann A, Komhoff M. Celecoxib dilates guinea-pig coronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5 inhibition. Cardiovasc Res 2007; 75:390-397.