Research Article
BibTex RIS Cite

Dipiron farelerde anksiyolitik-benzeri etkiler oluşturuyor mu?

Year 2019, Volume: 44 Issue: 3, 866 - 874, 30.09.2019
https://doi.org/10.17826/cumj.488406

Abstract



Amaç: Yakın zamanda parasetamol’ün anksiyolitik-benzeri etkileri olduğu ve bu etkilerine kannabinoid CB1 reseptörlerinin aracılık ettiği gösterilmiştir. Etkilerinde santral sinir sisteminin rolü olduğu uzun zamandır düşünülen ve etkileri açısından non-steroid anti-inflamatuvar ilaçlardan çok parasetamol ile benzerlik gösteren bir analjezik olan dipiron’un da antinosiseptif etkisinde kannabinoid sistemin rolü olduğu belirtilmiştir. Bu verilerden yola çıkarak dipiron’un anksiyolitik etki gösterebileceği düşünüldü; varsa bu etkisinde kannabinoid ve TRPV1 reseptörlerinin katkısının araştırılması planlandı.

Gereç ve Yöntem: Balb-c farelerde dipiron (150, 300, 600 mg/kg, i.p.) verildikten sonra üç odalı sosyallik ve sosyal yenilik testi, açık alan testi ve yükseltilmiş artı labirent testleri uygulanması, etki görülürse kannabinoid CB1 antagonisti AM251 (1 mg/kg i.p.), CB2 antagonisti SR 144528 (1 mg/kg i.p.) ve TRPV1 antagonisti kapsazepin (3 mg/kg i.p.) ile birlikte verilmesi düşünüldü. 

Bulgular: Dipiron herhangi bir dozunda davranış testlerinin (üç odalı sosyallik ve sosyal yenilik testi, açık alan testi ve yükseltilmiş artı labirent testi) hiçbirisinde etki göstermedi. Bu nedenle, dipiron ile birlikte kannabinoid CB1, CB2 ve TRPV1 reseptör antagonistlerinin birlikte uygulanacağı aşamaya geçilmedi.

Sonuç: Parasetamol’den farklı olarak, dipiron farelerde anksiyolitik-benzeri etkilere yol açmamaktadır. Deneysel modeller ve ölçüm yöntemlerindeki farklılıklar bu bulgularımızın nedeni olabilir.


References

  • Referans 1. Ulugol A. The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J. 2014;31:115-20. Referans 2. Schrot RJ, Hubbard JR. Cannabinoids: Medical implications. Annals of Medicine. 2016;48(3):128-41.
  • Referans 3. Wright S, Guy G. Licensed cannabis-based medicines: Benefits and risks. In: Handbook of Cannabis (Eds Pertwee R ): 373-92.New York: Oxford University Press; 2014. Referans 4. Ulugol A. Kannabinoidlerin klinikte kullanılışı ve terapötik hedefler. Türkiye Klinikleri Farmakoloji Özel Sayısı. 2018;6(1):42-50.
  • Referans 5. Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav R. 2017;76:56-66.
  • Referans 6. Marco EM, Perez-Alvarez L, Borcel E, Rubio M, Guaza C, Ambrosio E, et al. Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats. Behavioural Pharmacology. 2004;15(1):21-7.
  • Referans 7. Akman H, Aksu F, Gultekin I, Ozbek H, Oral U, Doran F, et al. A possible central antinociceptive effect of dipyrone in mice. Pharmacology. 1996;53(2):71-8.
  • Referans 8. Carlsson KH, Jurna I. The Role of Descending Inhibition in the Antinociceptive Effects of the Pyrazolone Derivatives, Metamizol (Dipyrone) and Aminophenazone (Pyramidon). N-S Arch Pharmacol. 1987;335(2):154-9. Referans 9. Gencer A, Gunduz O, Ulugol A. Involvement of descending serotonergic and noradrenergic systems and their spinal receptor subtypes in the antinociceptive effect of dipyrone. Drug Res. 2015;65(12):645-9.
  • Referans 10. Yilmaz I, Ulugol A. The Effect of Nitric Oxide Synthase Inhibitors on the Development of Analgesic Tolerance to Dipyrone in Mice. Int J Neurosci. 2009;119(6):755-64.
  • Referans 11. Kiroglu OE, Demirkol K, Berktas F, Yegani AA, Kirpik A, Maytalman E, et al. Dipyrone ameliorates behavioural changes induced by unpredictable chronic mild stress: gender differences. Clin Invest Med. 2016;39(6):S14-S20. Referans 12. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. European Journal of Pharmacology. 2007;573(1-3):214-5.
  • Referans 13. Ottani A, Ferraris E, Giuliani D, Mioni C, Bertolini A, Sternieri E, et al. Effect of sumatriptan in different models of pain in rats. European Journal of Pharmacology. 2004;497(2):181-6.
  • Referans 14. Mallet C, Daulhac L, Bonnefont J, Ledent C, Etienne M, Chapuy E, et al. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 2008;139(1):190-200.
  • Referans 15. Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, et al. Novel bioactive metabolites of dipyrone (metamizol). Bioorgan Med Chem. 2012;20(1):101-7.
  • Referans 16. Crunfli F, Vilela FC, Giusti-Paiva A. Cannabinoid CB1 receptors mediate the effects of dipyrone. Clin Exp Pharmacol P. 2015;42(3):246-55.
  • Referans 17. Elmas P, Ulugol A. Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone. J Neural Transm. 2013;120(11):1533-8. Referans 18. Schlosburg JE, Radanova L, Di Marzo V, Imming P, Lichtman AH. Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone (metamizol) in mice. Behavioural Pharmacology. 2012;23(7):722-6.
  • Referans 19. Paunescu H, Coman OA, Coman L, Ghita I, Georgescu SR, Draghia F, et al. Cannabinoid system and cyclooxygenases inhibitors. J Med Life. 2011;4(1):11-20.
  • Referans 20. Umathe SN, Manna SSS, Utturwar KS, Jain NS. Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors. Prog Neuro-Psychoph. 2009;33(7):1191-9.
  • Referans 21. Gould GG, Seillier A, Weiss G, Giuffrida A, Burke TF, Hensler JG, et al. Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. Prog Neuro-Psychoph. 2012;38(2):260-9.
  • Referans 22. Vane J, Botting R. Inflammation and the Mechanism of Action of Antiinflammatory Drugs. Faseb Journal. 1987;1(2):89-96.
  • Referans 23. Hamza M, Dionne RA. Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition. Curr Mol Pharmacol. 2009;2(1):1-14.
  • Referans 24. Alves DP, Duarte IDG. Involvement of ATP-sensitive K+ channels in the peripheral antinociceptive effect induced by dipyrone. Eur J Pharmacol. 2002;444(1-2):47-52.
  • Referans 25. Campos C, de Gregorio R, Garcia-Nieto R, Gago F, Ortiz P, Alemany S. Regulation of cyclooxygenase activity by metamizol. Eur J Pharmacol. 1999;378(3):339-47.
  • Referans 26. Dos Santos GG, Dias EV, Teixeira JM, Athie MC, Bonet IJ, Tambeli CH, et al. The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: Neuronal K channel opening and CB receptor activation. Eur J Pharmacol. 2014;741C:124-31.
  • Referans 27. Silva LCR, Romero TRL, Guzzo LS, Duarte IDG. Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs. Brazilian Journal of Medical and Biological Research. 2012;45(12):1240-3.
  • Referans 28. Vanegas H, Vazquez E, Tortorici V. NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System. Pharmaceuticals (Basel). 2010;3(5):1335-47.
  • Referans 29. Beirith A, Santos ARS, Rodrigues ALS, Creczynski-Pasa TB, Calixto JB. Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action. Eur J Pharmacol. 1998;345(3):233-45.
  • Referans 30. Ertin IH, Gunduz O, Ulugol A. Contribution of nociceptin/orphanin FQ receptors to the anti-nociceptive and hypothermic effects of dipyrone. Acta neuropsychiatrica. 2015;27(1):48-52. Referans 31. Siebel JS, Beirith A, Calixto JB. Evidence for the involvement of metabotropic glutamatergic, neurokinin 1 receptor pathways and protein kinase C in the antinociceptive effect of dipyrone in mice. Brain Research. 2004;1003(1-2):61-7. Referans 32. Moreira FA, Aguiar DC, Guimaraes FS. Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology. 2007;52(3):958-65.
  • Referans 33. Rubino T, Realini N, Castiglioni C, Guidali C, Vigano D, Marras E, et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex. 2008;18(6):1292-301.
  • Referans 34. Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, et al. Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology. 2006;31(12):2652-9. Referans 35. Haller J, Varga B, Ledent C, Barna I, Freund TF. Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice. European Journal of Neuroscience. 2004;19(7):1906-12. Referans 36. Rodgers RJ, Evans PM, Murphy A. Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behavioural Pharmacology. 2005;16(5-6):405-13.
  • Referans 37. Viveros MP, Marco EM, File SE. Endocannabinoid system and stress and anxiety responses. Pharmacology Biochemistry and Behavior. 2005;81(2):331-42.
  • Referans 38. Fowler CJ. NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs? Trends in Pharmacological Sciences. 2012;33(9):468-73.
  • Referans 39. de Lago E, Petrosino S, Valenti M, Morera E, Ortega-Gutierrez S, Fernandez-Ruiz J, et al. Effect of repeated systemic administration of selective inhibitors of endocannabinoid inactivation on rat brain endocannabinoid levels. Biochemical Pharmacology. 2005;70(3):446-52.

Does dipyrone produce anxiolytic-like effects in mice?

Year 2019, Volume: 44 Issue: 3, 866 - 874, 30.09.2019
https://doi.org/10.17826/cumj.488406

Abstract

Purpose: Paracetamol has been shown to exert anxiolytic-like effects mediated by endocannabinoids via cannabinoid CB1 receptors. Dipyrone is an analgesic with similar effects to paracetamol rather than non-steroidal anti-inflammatory drugs. Involvement of central structures to its effects are long under debate, whereas recent findings suggesting contribution of cannabinoid CB1 receptors to its antinociceptive effect support this argument. Taken together, the purpose of this study was to investigate whether dipyrone possesses anxiolytic-like behavior; contribution of cannabinoid CB1 and CB2 receptors and TRPV1 receptors will be determined in case of observing any effect of dipyrone in anxiety tests.

Material and Methods: Balb-c mice effects of dipyrone (150, 300, 600 mg/kg, i.p.) were assessed in three-chamber social interaction, open-field, elevated plus-maze and rota rod tests. The cannabinoid CB1 antagonist AM251 (1 mg/kg i.p.), the CB2 antagonist SR 144528 (1 mg/kg i.p.) and the TRPV1 antagonist capsazepine (3 mg/kg i.p.) were going to be administered before dipyrone injections if any effect of dipyrone occurs. 

Results: Dipyrone had no effect at any dose in behavioral tests (three-chamber social interaction, open-field, elevated plus-maze and rota rod tests). Therefore, dipyrone is not tested together with the cannabinoid CB1 and CB2 antagonists and the TRPV1 receptor antagonist.

Conclusion: Unlike paracetamol, dipyrone did not possess anxiolytic-like effects in mice. Discrepancies in experimental models and methodologies may be the reason of our results.


References

  • Referans 1. Ulugol A. The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J. 2014;31:115-20. Referans 2. Schrot RJ, Hubbard JR. Cannabinoids: Medical implications. Annals of Medicine. 2016;48(3):128-41.
  • Referans 3. Wright S, Guy G. Licensed cannabis-based medicines: Benefits and risks. In: Handbook of Cannabis (Eds Pertwee R ): 373-92.New York: Oxford University Press; 2014. Referans 4. Ulugol A. Kannabinoidlerin klinikte kullanılışı ve terapötik hedefler. Türkiye Klinikleri Farmakoloji Özel Sayısı. 2018;6(1):42-50.
  • Referans 5. Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav R. 2017;76:56-66.
  • Referans 6. Marco EM, Perez-Alvarez L, Borcel E, Rubio M, Guaza C, Ambrosio E, et al. Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats. Behavioural Pharmacology. 2004;15(1):21-7.
  • Referans 7. Akman H, Aksu F, Gultekin I, Ozbek H, Oral U, Doran F, et al. A possible central antinociceptive effect of dipyrone in mice. Pharmacology. 1996;53(2):71-8.
  • Referans 8. Carlsson KH, Jurna I. The Role of Descending Inhibition in the Antinociceptive Effects of the Pyrazolone Derivatives, Metamizol (Dipyrone) and Aminophenazone (Pyramidon). N-S Arch Pharmacol. 1987;335(2):154-9. Referans 9. Gencer A, Gunduz O, Ulugol A. Involvement of descending serotonergic and noradrenergic systems and their spinal receptor subtypes in the antinociceptive effect of dipyrone. Drug Res. 2015;65(12):645-9.
  • Referans 10. Yilmaz I, Ulugol A. The Effect of Nitric Oxide Synthase Inhibitors on the Development of Analgesic Tolerance to Dipyrone in Mice. Int J Neurosci. 2009;119(6):755-64.
  • Referans 11. Kiroglu OE, Demirkol K, Berktas F, Yegani AA, Kirpik A, Maytalman E, et al. Dipyrone ameliorates behavioural changes induced by unpredictable chronic mild stress: gender differences. Clin Invest Med. 2016;39(6):S14-S20. Referans 12. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. European Journal of Pharmacology. 2007;573(1-3):214-5.
  • Referans 13. Ottani A, Ferraris E, Giuliani D, Mioni C, Bertolini A, Sternieri E, et al. Effect of sumatriptan in different models of pain in rats. European Journal of Pharmacology. 2004;497(2):181-6.
  • Referans 14. Mallet C, Daulhac L, Bonnefont J, Ledent C, Etienne M, Chapuy E, et al. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 2008;139(1):190-200.
  • Referans 15. Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, et al. Novel bioactive metabolites of dipyrone (metamizol). Bioorgan Med Chem. 2012;20(1):101-7.
  • Referans 16. Crunfli F, Vilela FC, Giusti-Paiva A. Cannabinoid CB1 receptors mediate the effects of dipyrone. Clin Exp Pharmacol P. 2015;42(3):246-55.
  • Referans 17. Elmas P, Ulugol A. Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone. J Neural Transm. 2013;120(11):1533-8. Referans 18. Schlosburg JE, Radanova L, Di Marzo V, Imming P, Lichtman AH. Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone (metamizol) in mice. Behavioural Pharmacology. 2012;23(7):722-6.
  • Referans 19. Paunescu H, Coman OA, Coman L, Ghita I, Georgescu SR, Draghia F, et al. Cannabinoid system and cyclooxygenases inhibitors. J Med Life. 2011;4(1):11-20.
  • Referans 20. Umathe SN, Manna SSS, Utturwar KS, Jain NS. Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors. Prog Neuro-Psychoph. 2009;33(7):1191-9.
  • Referans 21. Gould GG, Seillier A, Weiss G, Giuffrida A, Burke TF, Hensler JG, et al. Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. Prog Neuro-Psychoph. 2012;38(2):260-9.
  • Referans 22. Vane J, Botting R. Inflammation and the Mechanism of Action of Antiinflammatory Drugs. Faseb Journal. 1987;1(2):89-96.
  • Referans 23. Hamza M, Dionne RA. Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition. Curr Mol Pharmacol. 2009;2(1):1-14.
  • Referans 24. Alves DP, Duarte IDG. Involvement of ATP-sensitive K+ channels in the peripheral antinociceptive effect induced by dipyrone. Eur J Pharmacol. 2002;444(1-2):47-52.
  • Referans 25. Campos C, de Gregorio R, Garcia-Nieto R, Gago F, Ortiz P, Alemany S. Regulation of cyclooxygenase activity by metamizol. Eur J Pharmacol. 1999;378(3):339-47.
  • Referans 26. Dos Santos GG, Dias EV, Teixeira JM, Athie MC, Bonet IJ, Tambeli CH, et al. The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: Neuronal K channel opening and CB receptor activation. Eur J Pharmacol. 2014;741C:124-31.
  • Referans 27. Silva LCR, Romero TRL, Guzzo LS, Duarte IDG. Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs. Brazilian Journal of Medical and Biological Research. 2012;45(12):1240-3.
  • Referans 28. Vanegas H, Vazquez E, Tortorici V. NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System. Pharmaceuticals (Basel). 2010;3(5):1335-47.
  • Referans 29. Beirith A, Santos ARS, Rodrigues ALS, Creczynski-Pasa TB, Calixto JB. Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action. Eur J Pharmacol. 1998;345(3):233-45.
  • Referans 30. Ertin IH, Gunduz O, Ulugol A. Contribution of nociceptin/orphanin FQ receptors to the anti-nociceptive and hypothermic effects of dipyrone. Acta neuropsychiatrica. 2015;27(1):48-52. Referans 31. Siebel JS, Beirith A, Calixto JB. Evidence for the involvement of metabotropic glutamatergic, neurokinin 1 receptor pathways and protein kinase C in the antinociceptive effect of dipyrone in mice. Brain Research. 2004;1003(1-2):61-7. Referans 32. Moreira FA, Aguiar DC, Guimaraes FS. Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology. 2007;52(3):958-65.
  • Referans 33. Rubino T, Realini N, Castiglioni C, Guidali C, Vigano D, Marras E, et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex. 2008;18(6):1292-301.
  • Referans 34. Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, et al. Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology. 2006;31(12):2652-9. Referans 35. Haller J, Varga B, Ledent C, Barna I, Freund TF. Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice. European Journal of Neuroscience. 2004;19(7):1906-12. Referans 36. Rodgers RJ, Evans PM, Murphy A. Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behavioural Pharmacology. 2005;16(5-6):405-13.
  • Referans 37. Viveros MP, Marco EM, File SE. Endocannabinoid system and stress and anxiety responses. Pharmacology Biochemistry and Behavior. 2005;81(2):331-42.
  • Referans 38. Fowler CJ. NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs? Trends in Pharmacological Sciences. 2012;33(9):468-73.
  • Referans 39. de Lago E, Petrosino S, Valenti M, Morera E, Ortega-Gutierrez S, Fernandez-Ruiz J, et al. Effect of repeated systemic administration of selective inhibitors of endocannabinoid inactivation on rat brain endocannabinoid levels. Biochemical Pharmacology. 2005;70(3):446-52.
There are 30 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Research
Authors

Ruhan Deniz Topuz 0000-0002-1520-3754

Özgür Gündüz This is me 0000-0002-2470-3021

Dikmen Dökmeci This is me 0000-0002-7685-127X

Çetin Hakan Karadağ This is me 0000-0002-4763-986X

Ahmet Ulugöl 0000-0003-4643-1124

Publication Date September 30, 2019
Acceptance Date January 13, 2019
Published in Issue Year 2019 Volume: 44 Issue: 3

Cite

MLA Topuz, Ruhan Deniz et al. “Dipiron Farelerde Anksiyolitik-Benzeri Etkiler oluşturuyor Mu?”. Cukurova Medical Journal, vol. 44, no. 3, 2019, pp. 866-74, doi:10.17826/cumj.488406.