Evaluation of Analgesic Tolerance Induced by Metamizole in the Writhing Test Model

Palabras clave: metamizole, writhing test, pain, tolerance


Analgesic tolerance is defined as the need for increasing doses to achieve the intended effect. In this paper we present experimental data from the search for analgesic tolerance induced by metamizole in a pain model induced by 0.9% acetic acid known as abdominal constriction test or Writhing test. The aim of this study was to identify the development of analgesic tolerance to metamizole in the Writhing test model. Experimental: groups of Balb/C mice 6±2 were used. They were administered metamizole in different protocols, and subsequently underwent a pain stimulus with 0.9% acetic acid via intraperitoneal, evaluated for 30 minutes and counting time of latency, number of abdominal stretches in order to rate pain response, subsequently naloxone was administered to look for signs of withdrawal. Our results demonstrated that there is a tendency to develop analgesic tolerance to metamizole after its repeated administration.


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Abdollahi, M., Karimpour, H., & Monsef-Esfehani, H. R. (2003). Antinociceptive effects of Teucrium polium L. total extract and essential oil in mouse writhing test. Pharmacological Research, 48(1), 31-35.

Akman, H., Aksu, F., Gültekin, İ., Özbek, H., Oral, U., Doran, F., & Baysal, F. (1996). A possible central antinociceptive effect of dipyrone in mice. Pharmacology, 53(2), 71-78.

Arcila-Herrera, H., Barragán-Padilla, S., Borbolla-Escoboza, J. R., Canto-Solís, A., Castañeda-Hernández, G., de León-González, M., ... & Vargas-Correa, J. B. (2004). Consensus of a Group of Mexican Experts: Efficacy and Safety of Metamizol (Dipirone). Gaceta Médica de México, 140(1), 99-102.

Andrade, S. E., Martinez, C., & Walker, A. M. (1998). Comparative safety evaluation of non-narcotic analgesics. Journal of clinical epidemiology, 51(12), 1357-1365.

Azorlosa, J. L., Stitzer, M. L., & Greenwald, M. K. (1994). Opioid physical dependence development: effects of single versus repeated morphine pretreatments and of subjects' opioid exposure history. Psychopharmacology, 114(1), 71-80.

Basbaum, A. I., & Fields, H. L. (1984). Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annual review of neuroscience, 7(1), 309-338.

Basbaum A.I. (1999). Spinal mechanisms of acute and persistent pain. Reg Anesth Pain Med; 24:59- 67.

Bhargava, H. N. (1994). Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. Pharmacological Reviews, 46(3), 293-324.

Besson, J. M., & Chaouch, A. T. H. M. A. N. E. (1987). Peripheral and spinal mechanisms of nociception. Physiological reviews, 67(1), 67-186.

Carlsson, K. H., Helmreich, J., & Jurna, I. (1986). Activation of inhibition from the periaqueductal grey matter mediates central analgesic effect of metamizol (dipyrone). Pain, 27(3), 373-390.

Cashman, J. N. (1996). The mechanisms of action of NSAIDs in analgesia. Drugs, 52, 13-23.

Cervero, F., & Laird, J. M. (1999). Visceral pain. The Lancet, 353(9170), 2145-2148.

Christie, M. J. (2008). Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. British journal of pharmacology, 154(2), 384-396.

Dafters, R., & Odber, J. (1989). Effects of dose, interdose interval, and drug-signal parameters on morphine analgesic tolerance: Implications for current theories of tolerance. Behavioral neuroscience, 103(5), 1082.

Dray, A. (1997). Peripheral mediators of pain. In The pharmacology of pain (pp. 21-41). Berlin, Heidelberg: Springer Berlin Heidelberg.

Doretto, M. C., Garcia-Cairasco, N., Pimenta, N. J. G., Souza, D. A., & Tatsuo, M. A. K. F. (1998). Dipyrone, a novel anticonvulsant agent? Insights from three experimental epilepsy models. Neuroreport, 9(10), 2415-2421.

Duarte Souza, J. F., Lajolo, P. P., Pinczowski, H., & Del Giglio, A. (2007). Adjunct dipyrone in association with oral morphine for cancer-related pain: the sooner the better. Supportive Care in Cancer, 15, 1319-1323.

Ergün, H., Uzbay, İ. T., Çelik, T., Kayir, H., Yeşilyurt, Ö., & Tulunay, F. C. (2001). Dipyrone inhibits ethanol withdrawal and pentylenetetrazol‐induced seizures in rats. Drug development research, 53(4), 254-259.

Feria M., (2008). Fármacos analgésicos antitérmicos y antiinflmatorios no esteroideos, antiartríticos en: Farmacología humana (Eds) Flórez J., Armijo J.A., Mediavillla A. 5ª. Edición, editorial Elsevier-Masson, 421-455.

Gawade, S. (2012). Acetic acid induced painful endogenous infliction in writhing test on mice. Journal of Pharmacology and Pharmacotherapeutics, 3(4), 348.

Groser Tilo, Emer Smyth y Garret A. FitzGerald. (2011). Antiinflamatorios, antipiréticos, analgésicos y farmacoterapia de la gota En: Bases farmacológicas de la terapéutica (Ed) Brunton, L. L., Chabner, B. A., & Knollmann, B. C.Goodman & Gilman: Las bases farmacológicas de la terapéutica. McGraw hill. McGRAW-HILL INTERAMERICANA EDITORES, S.A. de C.V., 12ª. Edición, pp: 959-1004.

Guyton Arthur C. (1977), Sensaciones somáticas: II. Dolor, dolor visceral, cefalea y temperatura. En tratado de fisiología médica, 5ª. edición, México, D.F. Ed. Interamericana, 662-677.

Hernández, N., & Vanegas, H. (2001). Antinociception induced by PAG-microinjected dipyrone (metamizol) in rats: involvement of spinal endogenous opioids. Brain research, 896(1-2), 175-178.

Hernández-Delgadillo, G. P., López-Muñoz, F. J., Salazar, L. A., & Cruz, S. L. (2003). Morphine and dipyrone co-administration delays tolerance development and potentiates antinociception. European journal of pharmacology, 469(1-3), 71-79.

Heishman, S. J., Stitzer, M. L., Bigelow, G. E., & Liebson, I. A. (1989). Acute opioid physical dependence in postaddict humans: naloxone dose effects after brief morphine exposure. Journal of Pharmacology and Experimental Therapeutics, 248(1), 127-134.

Hudspith, M. J., Siddall, P. J., & Munglani, R. (2006). Physiology of pain. Foundations of anesthesia, 267-285.

Ibarra, E. (2006). Una nueva definición de" dolor": un imperativo de nuestros días. Revista de la Sociedad Española del dolor, 13(2), 65-72.

Julius, D., & Basbaum, A. I. (2001). Molecular mechanisms of nociception. Nature, 413(6852), 203-210.

Kayan, S., & Mitchell, C. L. (1969). Further studies on the development of tolerance to the analgesic effect of morphine. Archives Internationales de Pharmacodynamie et de Therapie, 182(2), 287-294.

Kim, D. H., Fields, H. L., & Barbaro, N. M. (1990). Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes. Brain research, 516(1), 37-40.

Laird, J. M. A., Roza, C., & Olivar, T. (1998). Antinociceptive activity of metamizol in rats with experimental ureteric calculosis: central and peripheral components. Inflammation research, 47, 389-395.

Lorenzetti, B. B., & Ferreira, S. H. (1985). Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia. European journal of pharmacology, 114(3), 375-381.

Mayer D.J., Mao J. and Price D. (1995). The development of morphine tolerance and dependence is associated with traslocation of protein kinase C. Pain. 61:365-374.

Mercadante, S. (1999). Problems of long-term spinal opioid treatment in advanced cancer patients. Pain, 79(1), 1-13.

Millan, M. J. (2002). Descending control of pain. Progress in neurobiology, 66(6), 355-474.

Milligan, ED y Watkins, LR (2009). Papeles patológicos y protectores de la glía en el dolor crónico. La naturaleza revisa la neurociencia, 10 (1), 23-36.

Navarro Tobar, C. A. (2005). Estudios de la interacción entre paracetamol y metazimol en dolor experimiental térmico.

NOM-062-ZOO-1999, N. O. M., & LA PRODUCCION, E. T. P. (1999). Norma Oficial Mexicana NOM-062-ZOO-1999: Especificaciones técnicas para la producción, cuidado y uso de los animales de laboratorio.

Peñaranda Moren, M. M. (2006). Modulación opioide y nitridérgica de analgésicos en dolor experimental agudo.

Pérez Fuentes, J. (2020). Versión actualizada de la definición de dolor de la IASP: un paso adelante o un paso atrás. Revista de la Sociedad Española del Dolor, 27(4), 232-233.

Roberts L.J. and Morrow J.D. (2001). Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. Em: Goodman & Gilman´s. The Parmacological Basis of Terapeutics. Hardman J.G., Limbird L.E. y Goodman Gilman A. Ed. McGraw Hill, USA. Tenth Edition, 687-731.

Saelens, J. K., Granat, F. R., & Sawyer, W. K. (1971). The mouse jumping test--a simple screening method to estimate the physical dependence capacity of analgesics. Archives internationales de pharmacodynamie et de therapie, 190(2), 213-218.

Sunshine A. and Olson N.Z. (1994). Nonarcotic analgesics. En: Texbook of Pain. Wall P.D. and Melzak R. Ed. Churchill Livingstone, USA Third edition, 923-942.

Tony L. Yaksh y Mark S. Wallace (2011). Opioides, analgesia y tratamiento del dolor. En: Bases farmacológicas de la terapéutica (Ed) Brunton, L. L., Chabner, B. A., & Knollmann, B. C. Goodman & Gilman: Las bases farmacológicas de la terapéutica. McGraw hill. McGRAW-HILL INTERAMERICANA EDITORES, S.A. de C.V., 12ª. edición, pp:481-525.

Tortorici, V., Vásquez, E., & Vanegas, H. (1996). Naloxone partial reversal of the antinociception produced by dipyrone microinjected into the periaqueductal gray of rats. Possible involvement of medullary off-and on-cells. Brain research, 725(1), 106-110.

Tortorici, V., & Vanegas, H. (2000). Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal grey of rats. European Journal of Neuroscience, 12(11), 4074-4080.

Vanegas, H., & Tortorici, V. (2002). Opioidergic effects of nonopioid analgesics on the central nervous system. Cellular and molecular neurobiology, 22, 655-661.

Vasquez, E., & Vanegas, H. (2000). The antinociceptive effect of PAG-microinjected dipyrone in rats is mediated by endogenous opioids of the rostral ventromedial medulla. Brain research, 854(1-2), 249-252.

Watkins, LR y Maier, SF (2003). Glia: un nuevo objetivo de descubrimiento de fármacos para el dolor clínico. Reseñas de la naturaleza Descubrimiento de fármacos, 2 (12), 973-985.

Way, E. L., LOU, H. H., & Shen, F. H. (1969). Simultaneous quantitative assessment of morphine tolerance and physical dependence. Journal of Pharmacology and Experimental Therapeutics, 167(1), 1-8.

Weithmann, K. U., & Alpermann, H. G. (1985). Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade. Arzneimittel-forschung, 35(6), 947-952.

Williams, J. T., Christie, M. J., & Manzoni, O. (2001). Cellular and synaptic adaptations mediating opioid dependence. Physiological reviews, 81(1), 299-343.

Zimmermann, M. (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 16(2), 109-110.

Cómo citar
Garcia Mayorga , E. A., Hernández Degadillo , G. P., Rocha Aguirre , L. L., Lugo Garcia, A. D., & Castro Lugo, M. P. (2023). Evaluation of Analgesic Tolerance Induced by Metamizole in the Writhing Test Model. Ciencia Latina Revista Científica Multidisciplinar, 7(5), 3994-3520. https://doi.org/10.37811/cl_rcm.v7i5.7972