Original Scientific Article
The effect of metoclopramide on the antinociceptive, locomotor and neurobehavioral effects of metamizole in mice
Zena Sattam Hamed ,
Khalid Ahmed Shaban * ,
Ghada Abdul-Munem Faris

Mac Vet Rev 2024; 47 (2): 159 - 166

10.2478/macvetrev-2024-0027

Received: 26 May 2024

Received in revised form: 23 August 2024

Accepted: 26 August 2024

Available Online First: 27 September 2024

Published on: 15 October 2024

Correspondence: Khalid Ahmed Shaban,
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Abstract

Combining analgesic medications with distinct pharmacodynamics may result in effective analgesia and reduced adverse effects by lowering dosages of one or both medications. The objective was to investigate the nature of interactions of metoclopramide and metamizole by measuring the antinociceptive and neurobehavioral effects in mice. The drugs were administered intraperitoneally (ip) in mice. The antinociceptive effect was determined by the up-and-down method. Isobolographic analysis was performed by simultaneous injection of the two drugs at ED50 ratios of 1:1 and 0.5:0.5. The treated mice were also subjected to an open-field behavioral test as well as dorsal immobility and negative geotaxis behavioral paradigms. The ED50 of metoclopramide and metamizole were 33.71 and 43 mg/kg ip, respectively. Lower ED50 was established for metoclopramide and metamizole by 48.44% and 47.49%, respectively when given at a ratio of 0.5:0.5, and by 35.81% and 29.88%, respectively at a ratio of 1:1. The combined dose of metoclopramide and metamizole (8 and 10 mg/kg, ip, respectively) significantly decreased the open field-activity test in mice. This was observed by lower number of squares crossing compared to the control. Additionally, the drug combination resulted in a substantial increase in the duration of dorsal immobility response and delayed the negative geotaxis task when compared with the control group. The results indicated that the interaction between metoclopramide and metamizole in lower dose ratio with ED50 50:50, was synergistic in producing analgesia in mice with reduced risk for adverse reaction but with decreased behavioral and motor neuronal activity.

Keywords: metoclopramide, metamizole, antinociceptive effect, neurobehavioral, hot plate

References

1. Lee, A., Kuo, B. (2010). Metoclopramide in the treatment of diabetic gastroparesis.Expert Rev Endocrinol Metab. 5(5): 653-662. https://doi.org/10.1586/eem.10.41 PMid:21278804 PMCid:PMC3027056
2. Tavakoli, A., Mehrjerdi, H.K., Haghighi, A. (2009). Analgesic effects of metoclopramide following conventional ovariohysterectomy in bitches. Iranian J of Vet Sur. 4(1-2): 77-84.
3. Katzung, B.G. (2012). Basic and clinical pharmacology,12th ed. New York: McGraw-Hill
4. Harada, T., Hirosawa, T., Morinaga, K., Shimizu, T. (2017). Metoclopramide -induced serotonin syndrome. Intern Med. 56, 737- 739. https://doi.org/10.2169/internalmedicine.56.7727 PMid:28321081 PMCid:PMC5410491
5. Donald, C.P., Pharm, D. (2005). Veterinary drug handbook, 5th Ed. South State Avenue, Ames, Iowa: Blackwell Publishing Professional
6. Pang, W., Liu, Y.C., Maboudou, E., Chen, T.X., Chois, J.M., Liao, C.C., Wu, R.S. (2013). Metoclopramide improves the quality of tramadol PCA indistinguishable to morphine PCA: a prospective, randomized, double blind clinical comparison. Pain Med. 14(9): 1426-1434. https://doi.org/10.1111/pme.12166 PMid:23789747
7. Hamad, Z.S., Yahya, B.M. (2013). Identification and estimation of metoclopramide in rat blood by high performance liquid chromatography. Iraqi J Pharm. 13(1): 77-85. https://doi.org/10.33899/iphr.2013.66908 
8. Hofmeister, E.H., Egger, C.M. (2005). Evaluation of diphenhydramine as a sedative for dogs. J Am Vet Med Assoc. 226(7): 1092-1094. https://doi.org/10.2460/javma.2005.226.1092 PMid:15825733
9. Mohammad, F.K., Al-Baggou, B.K., Naser, A.S. (2012). Antinociception by metoclopramide, ketamine and their combinations in mice. Pharmacol Reports. 64(2): 299-304. https://doi.org/10.1016/S1734-1140(12)70768-5 PMid:22661179
10. Ai-Najmawy, T.A., Faris, G.M. (2018). Evaluation the antinociception of metoclopramide and their interaction with diphenhydramine in acute model of pain in male mice. Basrah J Vet Res. 3(17): 391-411.
11. Shaban, K.A., Ibrahim, M.H., Faris, G.A. (2020). Evaluation of the antinociceptive effect of xylazine and it’ s interaction with metoclopramide in the acute pain model in mice. Iraqi J Vet Sci. 43(2): 383-388. https://doi.org/10.33899/ijvs.2019.126070.1226 
12. Miljković, M.N., Rančić, N.K., Simić, R.M., Stamenković, D.M., Dragojević-Simić, V.M. (2018). Metamizole: current status of the safety and efficacy. Hosp Pharm. 5(3): 694-704. https://doi.org/10.5937/hpimj1803694M 
13. Leeuw, T.G., Dirckx, M., Gonzalez Candel, A., Scoones, G.P., Huygen, F.J.P.M., de Wildt, S.N. (2017). The use of dipyrone (metamizol) as an analgesic in children: what is the evidence? A review. Paediatr Anaesth. 27(12): 1193-1201. https://doi.org/10.1111/pan.13257 PMid:29024184
14. Chandrasekharan, N.V., Dai, H., Roos, K., Evanson, N.K., Tomsik, J., Elton, T., Simmons, D. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 99(21): 13926-13931. https://doi.org/10.1073/pnas.162468699 PMid:12242329 PMCid:PMC129799
15. Hernández-Delgadillo, G.P., Cruz, S.L. (2006). Endogenous opioids are involved in morphine and dipyrone analgesic potentiation in the tail flick test in rats. Eur J Pharmacol. 546(1-3): 54 59. https://doi.org/10.1016/j.ejphar.2006.07.027 PMid:16914138
16. Mohammad, F.K., Faris, G.A.M., Rayma, M.Sh. (2001). Analgesic and behavioral effects of xylazinedipyrone combination in mice. Iraqi J Vet Sci. 14, 183-189.
17. Ibrahem, K.A.S. (2013). The analgesic and neurobehavioral effects of dipyrone or tramadol and their interaction with xylazine in chicks model [Master Thesis]. University of Mosul, Mosul, Iraq
18. Bagheban, A.R., Nasiri, M., Majd, H.A., Shafaghi, B. (2010). Estimation of median effective dose of anti spasmodic medicine in adaptive design by combining the models. Koomesh. 11(3): 184-189.
19. Dixon, W.J. (1980). Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 20, 441-462. https://doi.org/10.1146/annurev.pa.20.040180.002301 PMid:7387124
20. Roy, R., Daula, A.S.U., Akter, A., Sultana, S., Barek, M.A., Liya, I.J., Basher, M.A. (2019). Antipyretic and anti-nociceptive effects of methanol extract of leaves of Fimbristylis miliacea in mice model. J Ethnopharmacol. 243, 112080. https://doi.org/10.1016/j.jep.2019.112080 PMid:31306693
21. Puig, M.M., Pol, O., Warner, W. (1996). Interaction of morphine and clonidine on gastrointestinal transit in mice. Anesthesiology 85(6): 1403-1412. https://doi.org/10.1097/00000542-199612000-00022 PMid:8968188
22. Tallarida, R.J. (2002). The interaction index: a measure of drug synergism. Pain 98(1-2): 163-168. https://doi.org/10.1016/S0304-3959(02)00041-6 PMid:12098628
23. Molinengo, L., Fundarò, A., Orsetti, M. (1989). The effect of chronic atropine administration on mouse motility and on Ach levels in the central nervous system. Pharmacol Biochem Behav. 32(4): 1075-1077. https://doi.org/10.1016/0091-3057(89)90085-3 PMid:2798531
24. Tatem, K.S,, Quinn, J.L., Phadke, A., Yu, Q., Gordish-dressman, H., Nagaraju, K. (2014). Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J Vis Exp. 29(91): 51785. https://doi.org/10.3791/51785 PMid:25286313 PMCid:PMC4672952
25. Molloy, A.G., Aronstam, R.S., Buccafusco, J.J. (1986). Selective antagonism by clonidine of the stereotyped and non-stereotyped motor activity elicited by atropine. Pharmacol Biochem Behav. 25(5): 985-988. https://doi.org/10.1016/0091-3057(86)90074-2 PMid:3786370
26. Mohammad, F.K., St, V.O. (1986). Behavioral and developmental effects in rats following in utero exposure to 2, 4-D/2, 4, 5-t mixture. Neurobehav Toxicol Teratol. 8(5): 551-560.
27. Yoshida, S., Esposito, G., Ohnishi, R., Tsuneoka, Y., Okabe, S., Kikusui, T., et al. (2013). Transport response is a filial-specific behavioral response to maternal carrying in C57BL/6 mice. Front Zool. 10(1): 50. https://doi.org/10.1186/1742-9994-10-50 PMid:23945354 PMCid:PMC3751433
28. Petrie, A., Watson, P. (2013). Statistics for veterinary and animal science. John Wiley & Sons
29. Fisher, A.A., Davis, M.W. (2002). Serotonin syndrome caused by selective serotonin reuptakeinhibitors metoclopramide interaction. Ann Pharmacother. 36(1): 67-71. https://doi.org/10.1345/aph.1A161 PMid:11816261
30. Ozucelik, D.N., Karaca, M.A., Sivri, B. (2005). Effectiveness of pre‐emptive metoclopramide infusion in alleviating pain, discomfort and nausea associated with nasogastric tube insertion: a randomized, double‐blind, placebo‐controlled trial. Int J Clin Pract. 59(12): 1422-1427. https://doi.org/10.1111/j.1368-5031.2005.00712.x PMid:16351674
31. Alves, D.P., Duarte, I.D.G. (2002). Involvement of ATP-sensitive K+ channels in the peripheral antinociceptive effect induced by dipyrone. Eur J Pharmacol. 444(1-2): 47-52. https://doi.org/10.1016/S0014-2999(02)01412-7 PMid:12191581
32. Hernández, N., Vanegas, H. (2001). Antinociception induced by PAG-microinjected dipyrone (metamizol) in rats: involvement of spinal endogenous opioids. Brain Res. 896(1-2): 175-178. https://doi.org/10.1016/S0006-8993(01)02085-6 PMid:11277989
33. Silva-Moreno, A., López-Muñoz, F.J., Cruz, S.L. (2009). D-propoxyphene and dipyrone coadministration produces greater antinociception and fewer adverse effects than single treatments in rats. Eur J Pharmacol [Internet]. 607(1-3): 84-90. https://doi.org/10.1016/j.ejphar.2009.02.010 PMid:19232342
34. Hedenmalm, K., Spigset, O. (2002). Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol. 58(4): 265-274. https://doi.org/10.1007/s00228-002-0465-2 PMid:12136373
35. Gould, S., Fulton, R., Koller, D. (2009). Decomposing a scene into geometric and semantically consistent regions. Proceedings of IEEE Int Conf Comput Vis. 1-8. https://doi.org/10.1109/ICCV.2009.5459211 
36. Botting, R., Ayoub, S. (2005). COX-3 and the mechanism of action of paracetamol/ acetaminophen. Prostaglandins Leukot Essent Fatty Acids. 72(2): 85-87. https://doi.org/10.1016/j.plefa.2004.10.005 PMid:15626590
37. Rang, H.P., Dale, M.M., Ritter, J.M., Moore, P.K. (2003). Pharmacology 5th Ed. Edinburgh: Churchill Livingstone

Copyright

© 2024 Hamed Z.S. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Conflict of Interest Statement

The authors declared that they have no potential lict of interest with respect to the authorship and/or publication of this article.

Citation Information

Macedonian Veterinary Review. Volume 47, Issue 2, Pages 159-166, e-ISSN 1857-7415, p-ISSN 1409-7621, DOI: 10.2478/macvetrev-2024-0027

The all content of the Macedonian Veterinary Review, except where otherwise noted, is licensed under a Creative Commons Attribution License.