Dipiron’un Analjezik Aktivitesi Üzerine H2S’in Etkilerinin Sıçanlarda Araştırılması

Year 2020, Volume: 2 Issue: 2, 90 - 96, 10.07.2020

Kevser Erol Çiğdem Çengelli Ünel Mahsum Ayaz Enes Yeşiltuna Ezgi Demir Hamza Dalçınar Bengihan Özcan

Abstract

Dipiron antipiretik, analjezik ve antiinflamatuvar etkileri olan pirazolon türevi bir ilaçtır. Postoperatif ağrı, kanser ağrısı, kolik ağrıları ve migren tedavisinde kullanılmaktadır. Analjezik etkisinin santral ve periferik yolla olduğu bilinmektedir. İstenmeyen ciddi yan etkileri olabilir. Hidrojen sülfür (H2S) aktif-radikal bir gazdır. Somatik, nöropatik ve viseral ağrı üzerine etkisi olduğu, inflamasyonu azalttığı gözlenmiştir. Dipironun santral ve periferik antinosiseptif etkileri ve bu etkilerde H2S’in katkısı değerlendirilmiştir. Otuz adet erkek Sprague-Dawley sıçan kullanılmıştır. İlaç uygulamasından 30 dakika önce tail clip ve hot plate test ölçümleri alınıp, kontrol grubuna serum fizyolojik, diğer gruplara Dipiron (50-100 mg/kg, i.p); NaHS (5mg/kg, i.p); NaHS (5mg/kg, i.p) + Dipiron (50mg/kg, i.p) verilmiştir. Uygulamadan bir saat sonra ölçümler tekrarlanmış, %0.6 asetik asid 60 mg/kg ip verildikten 5 dakika sonra kıvranma sayıları 10 dakika boyunca kaydedilmiştir. Latens, %MPE (olası maksimal etki) ve kıvranma sayısı kaydedilmiştir. İki ve tek yönlü ANOVA testi kullanılmıştır. 

Dipiron tail clip testinde anlamlı antinosiseptif etki göstermezken, 100 mg/kg dozda hot plate ve kıvranma testinde belirgin analjezik etki göstermiştir. NaHS, hot plate testinde latensi anlamlı uzatmış, tek başına kıvranma testinde belirgin aktivite göstermemiştir. 50 mg/kg dipiron ile kombine edildiğinde hot plate ve kıvranma testinde 100 mg/kg dipironun tek başına oluşturduğu etkiden daha fazla analjezik etki oluşturmuştur. Dipiron (50-100 mg/kg) santral yolla antinosiseptif etki göstermiş, 50 mg/kg dipiron periferik yolla etki gösterememiştir. NaHS santral antinosiseptif etki gösterip, periferik yolla gösterememiştir. NaHS (50 mg/kg) dipiron ile kombine edildiğinde antinosiseptif etkisi santral ve periferik yolla (100 mg/kg) dipironun etkisi kadar olmuştur. H2S dipironun analjezik etkisini santral ve periferik yolla artırdığı düşünülmektedir. 

Keywords

Antinosiseptif etki, dipiron

The Effects of H2S on The Analgesic Activity of Dipyrone in Rats

Abstract

Dipyrone is an analgesic, antipyretic and antiinflammatory drug that has been used for treating postopertive, colic, cancer pain, and migraine. It has some adverse effects such as of bone morrow suppression, sodium and water retention, and gastroenteropathy. Hydrogen sulfide (H2S) is a active-radical gas. The precursors of H2S were reported to overcome some drug side-effects. H2S was also shown to have activity against several pain-related situations. Study aimed to evaluate the contribution of H2S on central and peripheral antinociceptive activity of dipyrone. Male six weeks old Sprague Dawley rats were divided into five groups (n=6): Control (Saline, ip); dipyrone (50 or 100 mg/kg i.p); NaHS (5mg/kg i.p); NaHS (5mg/kg) + dipyrone (50 mg/kg). Tail clip and hot plate tests were applied to the animals 30 minutes before and one hour after the drug injections. Five minutes after the injection of 60 mg/kg acetic acid (%0,6), stretching number was counted for ten minutes. The results were expressed as mean±SEM of latency, %MPE (maximal possible effect) and stretching number. One way and two way ANOVA tests were used for statistical analysis. P<0.05 was accepted as significant. Both doses of dipyrone did not have a significant activity on tail clip test, but 100 mg/kg dipyrone showed significant antinociceptive activity on hot plate and stretching tests. NaHS (5 mg/kg) was increased latency only on hot plate test. But the combination of NaHS with dipyrone has significant antinociceptive activity. It seems that H2S increased the antinociceptive activity of dipyrone both central and peripherally.

Keywords

Antinociceptive activity, dipyrone

References

• 1. Derry S, Faura C, Edwards J, McQuay HJ, Moore RA. Single-dose dipyrone for acute postoperative pain. Cochrane Database Syst Rev. 2013;CD003227
• 2. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL 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 2002;99:13926-31.
• 3. Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nu¨sing R, Imming P, et al. Novel bioactive metabolites of dipyrone (metamizol). Bioorg Med Chem 2012;20:101-7
• 4. Tortorici V, Vanegas H Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal grey of rats. Eur J Neurosci 2000;12:4074-80
• 5. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002;58:265-74.
• 6. Kötter, T., da Costa, B. R., Fässler, M., Blozik, E., Linde, K., Jüni, P., Reichenbach, S., Scherer, M et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PloS one, 2015;10:e0122918.
• 7. Chávez-Pina A.E. et. al. Inhibition of Endogenous Hydrogen Sulfide Synthesis by PAG Protects Against Ethannol-Induced Gastric Damage in The Rat. Eur. Journal of Pharmacoloy 2010;630:131-6
• 8. Distrutti E. Hydrogen sulphide and pain. Inflamm Allergy Drug Targets. 2011;10:123-32. 9. Cenac N. et al., A novel orally administered trimebutine compound (GIC-1001) is anti-nociceptive and features peripheral opioid agonistic activity and Hydrogen Sulphide-releasing capacity in mice. Eur J Pain 2016;20:723-30
• 10. DIEF A.E., Hydrogen sulfide releasing naproxen offers better anti-inflammatory and chondroprotective effect relative to naproxen in a rat model of zymosan induced arthritis. European Review for Medical and Pharmacological Sciences 2015;19:1537-46
• 11. Mehanna MM, Domiati S, Nakkash Chmaisse H, El Mallah A. Antinociceptive effect of tadalafil in various pain models: Involvement of opioid receptors and nitric oxide cyclic GMP pathway. Toxicol Appl Pharmacol. 2018;352:170-5.
• 12. Kuraishi, Y.; Harada, Y.; Aratani, S.; Satoh, M.; Takagi, H. Involvement of the spinal noradrenergic and serotonergic systems in morphine analgesia: the differences in mechanical and thermal algesic tests. Brain Res. 1983;273:245–52.
• 13. Koster, R., Anderson, M. and De Beer, E.J. Acetic Acid for Analgesic Screening. Federation Proceedings, 1959;18:412-7.
• 14. 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 (Stuttg). 2015;65:645-9.
• 15. Laird JM, Roza C, Olivar T. Antinociceptive activity of metamizol in rats with experimental ureteric calculosis: central and peripheral components. Inflamm Res. 1998;47:389-95.
• 16. Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92:791-896.
• 17. Li M, Li J, Zhang T, Zhao Q, Cheng J, Liu B, Wang Z, Zhao L, Wang C. Syntheses, et al toxicities and anti-inflammation of H(2)S-donors based onnon-steroidal anti-inflammatory drugs. Eur J Med Chem. 2017;138:51-65.
• 18. Pozsgai G, Payrits M, Sághy É, Sebestyén-Bátai R, Steen E, Szőke É, Sándor Z, Solymár M, Garami A, Orvos P, Tálosi L, Helyes Z, Pintér E. Analgesic effect of dimethyl trisulfide in mice is mediated by TRPA1 and sst(4) receptors. Nitric Oxide. 2017;65:10-21.
• 19. Shefa U, Yeo SG, Kim MS, Song IO, Jung J, Jeong NY, Huh Y. Role of Gasotransmitters in Oxidative Stresses, Neuroinflammation, and Neuronal Repair. Biomed Res Int. 2017:1689341.