The effect of verapamil, nifedipine and diltiazem on formalin-induced pain response in mice

Subject Areas : Veterinary Clinical Pathology

M.H Khayat Nouri ¹ ( Department of Basic Sciences, Faculty of Veterinary Medicine, Islamic Azad University-Tabriz Branch, Tabriz, Iran )
جواد Mahmody ² ( Graduate of Veterinary Pharmacology, Faculty of Veterinary Medicine, Islamic Azad University-Science and Research Branch, Tehran, Iran )
M.R Hoseinchi Ghareaghaji ³ ( Department of Basic Sciences, Faculty of Veterinary Medicine, Islamic Azad University-Urmia Branch, Urmia, Iran )

Received: 2009-01-19 Accepted : 2009-08-23 Published : 2009-11-22

Keywords: Mice, Verapamil, Nifedipine, Diltiazem, pain, Formalin,

Abstract :

Voltage-gated calcium channels play a major role in the control of cellular processes in cardiac, vascular and neuronal tissues. Verapamil, nifedipine and diltiazem are calcium channel blockers widely used in the treatment of cardiovascular ailments in humans. A number of studies have shown that calcium channel blockers have antinociception and antiinflammatory effects in a range of animal models (but not in all animal models). The aim of this study was to investigate the effect of verapamil, nifedipine and diltiazem on formalin-induced pain and inflammation in mice. In this experimental study, verapamil, nifedipine and diltiazem (10 mg/kg) were intraperitoneally injected 30 minutes before the injection of 20µl of 5% formalin solution into the paw region. The time of licking and biting of injected paw was measured as pain response at 5 minute intervals for 1 hour. The results showed that formalin induced a biphasic pain response (first phase: 0-5 and second phase: 20-45 minute after injection). Intraperitoneal injection of verapamil, nifedipine and diltiazem before formalin reduced the second phase (inflammatory pain) of pain response significantly (p<0.05) and only verapamil reduced the first phase (neurogenic pain) of pain response significantly (p<0.05). Based on the results of this study it can be concluded that verapamil, nifedipine and diltiazem possess antinociceptive and antiinflammatory activity probably via a decrease in calcium influx that in turn interferes with the release of neurotransmitters and other substances that promote nociception and inflammation.

References:

1. تمدنفرد، ا. و مجتهدین، ع. (1383): اثر تزریق داخل صفاقی سایمتیدین بر پاسخ درد ناشی از فرمالین در موش‌های سوری، مجله دانشکده دامپزشکی دانشگاه تهران، دوره 59، شماره 4، صفحات: 378-373.


2. Choi, S.S., Lee, J.K. and Suh, H.W. (2001): Anti nociceptive profiles of aspirin and acetaminophen in formalin, substance P and glutamate pain models. Brain Res., 921(1-2): 233-239.


3. Diaz, A. and Dickenson, A.H. (1997): Blockade of spinal N- and P-type, but not L–type, calcium channels inhibits the excitability of rat dorsal horn neurons produced by subcutaneous formalin inflammation. Pain, 69(1-2): 93-100.


4. Grossman, E. and Messerli, F.H. (2004): Calcium antagonists. Prog. Cardiovas. Dis., 47(1): 34-57.


5. Hockerman, G.H., Peterson, B.Z., Johnson, B.D. and Catterall, W. (1997): Molecular determinants of drug binding and action on L-type calcium channels. Annu. Rev. Pharmacol. Toxicol., 37: 361-396.


6. Kulak, W., Sobaniec, W., Wojtal, K. and Czuczwar, S.J. (2004): Calcium modulation in epilepsy. Pol. J. Pharmacol., 56(1): 29-41.


7. Martin, M.I., Del Val V.L., Colado, M.I., Goicoechea, C. and Alfaro, M.J. (1996): Behavioral and analgesic effects induced by administration of nifedipine and nimodipine. Pharmacol. Biochem. Behav., 55(1): 93-98.


8. Ness, T.J. (1999): Models of visceral nociception. ILAR J, 40(3): 119-128.


9. Pathirathna, S., Brimelow, B.C., Jagodic, M.M., Krishnan, K., Jiang, X., Zorumski, C.F., et al. (2005): New evidence that both T-type calcium channels and GABA_A channels are responsible for the potent peripheral analgesic effects of 5-reduced neuro active steroids. Pain, 114(3): 429-443.


10. Porro, C.A. and Cavazzuti, M. (1993): Spatial and temporal aspects of spinal cord and brainstem activation in the formalin pain model. Prog. Neurobiol., 41(5): 565-607.


11. Ren, K. and Dubner, R. (1999): Inflammatory models of pain and hyperalgesia. ILARJ, 40(3): 111-118.


12. Ryan, S.G. (1999): Ion channels and the genetic contribution to epilepsy. J. Child Neurol., 14(1): 58-66.


13. Shutov, L., Kruglikov, I., Gryshchenko, O., Khomula, E., Viatchenko-Karpinski, V., Belan, P., et al. (2006): The effect of nimodipine on calcium homeostasis and pain sensitivity in diabetic rats. Cell Mol. Neurobiol., 26(7-8): 1541-1557.


14. Tjolsen, A., Berge, O.G., Hunskaar, S., Rosland, J.H. and Hole, K. (1992): The formalin test: an evaluation of the method. Pain, 51(1): 5-17.


15. Todorvic, S.M., Pathirathna, S., Meyenburg, A. and Jevtovic-Todorovic, V. (2004): Mechanical and thermal anti-nociception in rats after systemic administration of verapamil. Neurosci., Lett., 360(1-2): 57-60.


16. Zbuzek, V.K., Cohen, B. and Wu, W. (1997): Anti-nociceptive effect of nifedipine and verapamil tested on rats chronically exposed to nicotine and after its withdrawal. Life Sci., 60(19): 1651-1658.