TOFİSOPAM’IN OPİOİDERJİK SİSTEM ARACILIKLI ANTİNOSİSEPTİF ETKİNLİĞİ

Yıl 2022, , 712 - 727, 30.09.2022

Nazlı Turan , Umut İrfan Üçel , Cevşen Yazıcı , Ümide Demir Özkay , Özgür Devrim Can

https://doi.org/10.33483/jfpau.1085314

Öz

Amaç: Bu çalışmada Tofisopam’ın antinosiseptif etkinlik potansiyelinin araştırılması ve bu etkiye opioiderjik sistemin olası katılımının aydınlatılması amaçlanmıştır.
Gereç ve Yöntem: Tofisopam’ın (25 ve 50 mg/kg) antinosiseptif etkinlik potansiyeli sıcak plaka ve asetik asid ile indüklenen kıvranma testleri ile araştırılmış; farelerin motor koordinasyonu üzerindeki olası etkileri ise Rota-rod testi ile değerlendirilmiştir.
Sonuç ve Tartışma: Tofisopam 50 mg/kg dozda, farelerin sıcak plaka testlerindeki reaksiyon sürelerini anlamlı ölçüde uzatmış; kıvranma testlerinde ise kıvranma davranışlarının sayılarını azaltmıştır. Bu bulgular Tofisopam’ın santral ve periferik mekanizmalar aracılıklı antinosiseptif aktiviteye sahip olduğuna işaret etmiştir. Tofisopam farelerin motor aktivitelerinde anlamlı bir değişikliğe neden olmamıştır. Antinosiseptif etkiye opioid reseptörlerin olası katılımını araştırmak amacı ile yapılan nalokson ön-uygulamaları Tofisopam’ın antinosiseptif aktivitesini ortadan kaldırmıştır. Etkiye aracılık eden opioid reseptör alt-tiplerinin aydınlatılması amacıyla naloksonazin (μ-opioid reseptör blokörü), naltrindol (δ-opioid reseptör blokörü) ve nor-binaltorfimin (ҡ-opioid reseptör blokörü) ile mekanistik çalışmalar yapılmıştır. Her üç ajan da Tofisopam’ın antinosiseptif etkisini antagonize etmiştir. Elde edilen bu bulgular Tofisopam’ın 50 mg/kg dozdaki antinosiseptif etkinliğine μ-, δ- ve ҡ-oipiod reseptörlerin aracılık ettiğini ortaya koymuştur.

Anahtar Kelimeler

Analjezi, asetik asid ile indüklenen kıvranma testi, opioiderjik reseptör, sıcak plaka testi, tofisopam

Destekleyen Kurum

Anadolu Üniversitesi

Proje Numarası

1808S277

Teşekkür

Bu araştırma, Anadolu Üniversitesi Bilimsel Araştırma Projeleri Komisyonu tarafından desteklenmiştir (Proje Numarası: 1808S277).

OPIOIDERGIC SYSTEM-MEDIATED ANTINOCICEPTIVE ACTIVITY OF TOFISOPAM

Öz

Objective: In this study, it was aimed to investigate the antinociceptive activity potential of Tofisopam and to elucidate the possible involvement of opioid system in this effect.
Material and Method: The antinociceptive efficacy potential of Tofisopam (25 and 50 mg/kg) was evaluated by hot-plate and acetic acid-induced writhing tests; while possible effects of this drug on the motor coordination of mice were evaluated with the Rota-rod tests.
Result and Discussion: Tofisopam at a dose of 50 mg/kg significantly prolonged the reaction times of mice in hot-plate tests and reduced the number of writhing behaviors in writhing tests. These findings indicated that Tofisopam has antinociceptive activity mediated by central and peripheral mechanisms. Tofisopam did not change the motor activities of mice. Pre-administration of naloxone to investigate the possible involvement of opioid receptors in the antinociceptive effect abolished the antinociceptive activity of Tofisopam. To elucidate the opioid receptor subtypes mediating the effect, mechanistic studies were carried out with naloxonazine (μ-opioid receptor blocker), naltrindole (δ-opioid receptor blocker) and nor-binaltorphimine (ҡ-opioid receptor blocker). All agents antagonized the antinociceptive effect of Tofisopam. Obtained findings revealed that Tofisopam at a dose of 50 mg/kg have antinociceptive activity mediated by μ-, δ- and ҡ-oipiod receptors.

Anahtar Kelimeler

Analgesia, acetic acid-induced writhing test, hot-plate test, opioidergic receptor, tofisopam

Proje Numarası

1808S277

Kaynakça

• 1. Szénási, G., Hársing Jr, L.G. (2004). Pharmacology and prospective therapeutic usefulness of negative allosteric modulators of AMPA receptors. Drug Discovery Today: Therapeutic Strategies, 1(1), 69 – 76. [CrossRef]
• 2. Hamed, A., Skórzewska, A., Lehner, M., Płaźnik, A. (2007). Tofizopam. W poszukiwaniu mechanizmów działania 2,3-benzodiazepin. Farmakoterapia w Psychiatrii i Neurologii, 2, 109 – 117. [CrossRef]
• 3. Rx Media Pharma® (2022). İnteraktif İlaç Bilgi Kaynağı. Erişim tarihi: 20.02.2022.
• 4. Üçel, U.İ., Can, Ö.D., Özkay, Ü.D., Ulupinar, E. (2020). Antiamnesic effects of tofisopam against scopolamine-induced cognitive impairments in rats. Pharmacology Biochemistry and Behavior, 190, 172858. [CrossRef]
• 5. Horváth, E.J., Salamon, C., Bakonyi, A., Fekete, M.I., Palkovits, M. (1999). [(3)H]girisopam, a novel selective benzodiazepine for the 2, 3-benzodiazepine binding site. Brain Research Protocols, 4(2), 230 – 235. [CrossRef]
• 6. Horváth, E.J., Horváth, K., Hámori, T., Fekete, M.I., Sólyom, S., Palkovits, M. (2000). Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia. Progress in Neurobiology, 60(4), 309 – 342. [CrossRef]
• 7. Szegó, J., Somogyi, M., Papp, E. (1993). Szemelvények a Grandaxin klinikai-farmakológiai és klinikai vizsgálataiból [Excerpts from the clinical-pharmacologic and clinical studies of Grandaxin]. Acta Pharmaceutica Hungarica, 63(2), 91 – 98. [CrossRef]
• 8. Rundfeldt, C., Socala, K., Wlaź, P. (2010). The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. Journal of Neural Transmission (Vienna), 117(11), 1319 – 1325. [CrossRef]
• 9. Leventer, S.M., Raudibaugh, K., Frissora, C.L., Kassem, N., Keogh, J.C., Phillips, J., Mangel, A.W. (2008). Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome. Alimentary Pharmacology and Therapeutics, 27(2), 197 – 206. [CrossRef]
• 10. Petócz, L. (1993). Pharmacologic effects of tofizopam (Grandaxin). Acta Pharmaceutica Hungarica, 63(2), 79 – 82.
• 11. Fekete, M.I., Horváth, K., Kedves, R., Máté, I., Székely, J.I., Szentkuti, E. (1997). Selective interaction of homophtalazine derivatives with morphine. European Journal of Pharmacology, 331(2-3), 175 – 183. [CrossRef]
• 12. Pellow, S., File, S.E. (1986). Is tofisopam an atypical anxiolytic?. Neuroscience & Biobehavioral Reviews, 10, 221 – 227. [CrossRef]
• 13. Bernard, P., Dufresne-Favetta, C., Favetta, P., Do, Q.T., Himbert, F., Zubrzycki, S., Scior, T., Lugnier, C. (2008). Application of drug repositioning strategy to tofisopam. Current Medicinal Chemistry, 15(30), 3196 – 3203. [CrossRef]
• 14. Levy, R.A., Goldstein, B.D. (1981). Analgesia following microinjection of phosphodiesterase inhibitors at brainstem sites. Pharmacology Biochemistry and Behavior, 15(3), 501 – 504. [CrossRef]
• 15. Araiza-Saldaña, C.I., Reyes-García, G., Bermúdez-Ocaña, D.Y., Pérez-Severiano, F., Granados-Soto, V. (2005). Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats. European Journal of Pharmacology, 527(1-3), 60 – 70. [CrossRef]
• 16. Salehi, F., Hosseini-Zare, M.S., Aghajani, H., Seyedi, S.Y., Hosseini-Zare, M.S., Sharifzadeh, M. (2017). Effect of bucladesine, pentoxifylline, and H-89 as cyclic adenosine monophosphate analog, phosphodiesterase and protein kinase A inhibitor on acute pain. Fundamental & Clinical Pharmacology, 31(4), 411 – 419. [CrossRef]
• 17. Fujita, M., Tamano, R., Yoneda, S., Omachi, S., Yogo, E., Rokushima, M., Shinohara, S., Sakaguchi, G., Hasegawa, M., Asaki, T. (2018). Ibudilast produces anti-allodynic effects at the persistent phase of peripheral or central neuropathic pain in rats: Different inhibitory mechanism on spinal microglia from minocycline and propentofylline. European Journal of Pharmacology, 833, 263 – 274. [CrossRef]
• 18. Mehanna, M.M., Domiati, S., Nakkash Chmaisse, H., El Mallah, A. (2018). Antinociceptive effect of tadalafil in various pain models: Involvement of opioid receptors and nitric oxide cyclic GMP pathway. Toxicology and Applied Pharmacology, 352, 170 – 175. [CrossRef]
• 19. Rojewska, E., Piotrowska, A., Jurga, A., Makuch, W., Mika, J. (2018). Zaprinast diminished pain and enhanced opioid analgesia in a rat neuropathic pain model. European Journal of Pharmacology, 839, 21 – 32. [CrossRef]
• 20. Kumar, A., Jain, N.K., Kulkarni, S.K. (2000). Analgesic and anti-inflammatory effects of phosphodiesterase inhibitors. Indian Journal of Experimental Biology, 38(1), 26 – 30. [CrossRef]
• 21. Jain, N.K., Patil, C.S., Singh, A., Kulkarni, S.K. (2001). Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Brain Research, 909(1-2), 170 – 178. [CrossRef]
• 22. Jain, N.K., Patil, C.S., Singh, A., Kulkarni, S.K. (2003). Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine. Pharmacology, 67(3), 150 – 156. [CrossRef]
• 23. Kim, H.K., Kwon, J.Y., Yoo, C., Abdi, S. (2015). The analgesic effect of rolipram, a phosphodiesterase 4 inhibitor, on chemotherapy-induced neuropathic pain in rats. Anesthesia & Analgesia, 121(3), 822 – 828. [CrossRef]
• 24. Dunham, N.W., Miya, T.S. (1957). A note on a simple apparatus for detecting neurological deficit in rats and mice. Journal of the American Pharmaceutical Association (Scientific ed.), 46(3), 208 – 209. [CrossRef]
• 25. Adzu, B., Amos, S., Dzarma, S., Wambebe, C., Gamaniel, K. (2000). Effect of Zizypus spina-christi wild aqueous extract on the central nervous system in mice. Journal of Ethnopharmacology, 79(1), 13 – 16. [CrossRef]
• 26. Ozawa, M., Nakada, Y., Sugimachi, K., Yabuuchi, F., Akai, T., Mizuta, E., Kuno, S., Yamaguchi, M. (1994). Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates. Japanese Journal of Pharmacology, 64(3), 179 – 188. [CrossRef]
• 27. Woolfe, G., Mcdonald, A.D. (1944). The evaluation of analgesic action of pethidine hydrochloride (Demerol). Journal of Pharmacology and Experimental Therapeutics, 80(3), 300 – 307. [CrossRef]
• 28. Kasap, M., Can, Ö.D. (2016). Opioid system mediated anti-nociceptive effect of agomelatine in mice. Life Sciences, 163, 55 – 63. [CrossRef]
• 29. Koster, R., Anderson, M., Beer, E.J. (1959). Acetic acid for analgesic screening. Federation Proceedings, 18, 412 – 418.
• 30. Demir Özkay, U., Can, O.D. (2013). Anti-nociceptive effect of vitexin mediated by the opioid system in mice. Pharmacology Biochemistry and Behavior, 109, 23 – 30. [CrossRef]
• 31. Cartmell, S.M., Gelgor, L., Mitchell, D. (1991). A revised rotarod procedure for measuring the effect of antinociceptive drugs on motor function in the rat. Journal of Pharmacological Methods, 26(2), 149 – 159. [CrossRef]
• 32. Le Bars, D., Gozariu, M., Cadden, S.W. (2001). Animal models of nociception. Pharmacological Reviews, 53(4), 597 – 652. [CrossRef]
• 33. López-Canul, M., Comai, S., Domínguez-López, S., Granados-Soto, V., Gobbi, G. (2015). Antinociceptive properties of selective MT2 melatonin receptor partial agonists. European Journal of Pharmacology, 764, 424 – 432. [CrossRef]
• 34. Wong, C.H., Day, P., Yarmush, J., Wu, W., Zbuzek, U.K. (1994). Nifedipine induced analgesic after epidural injections in rats. Anesthesia & Analgesia, 79(2), 303 – 306. [CrossRef]
• 35. Gabra, B.H., Sirois, P. (2003). Beneficial effect of chronic treatment with the selective bradykinin B1 receptor antagonists, R-715 and R-954, in attenuating streptozotocin-diabetic thermal hyperalgesia in mice. Peptides, 24(8), 1131 – 1139. [CrossRef]
• 36. De Souza, M.M., Pereira, M.A., Ardenghi, J.V., Mora, T.C., Bresciani, L.F., Yunes, R.A., Delle Monache, F., Cechinel-Filho, V. (2009). Filicene obtained from Adiantum cuneatum interacts with the cholinergic, dopaminergic, glutamatergic, GABAergic, and tachykinergic systems to exert antinociceptive effect in mice. Pharmacology Biochemistry and Behavior, 93(1), 40 – 46. [CrossRef]
• 37. Park, S.H., Sim, Y.B., Kang, Y.J., Kim, S.S., Kim, C.H., Kim, S.J., Seo, J.Y., Lim, S.M., Suh, H.W. (2012). Hop extract produces antinociception by acting on opioid system in mice. Korean Journal of Physiology & Pharmacology, 16(3), 187 – 192. [CrossRef]
• 38. Coelho, L.P., Reis, P.A., de Castro, F.L., Gayer, C.R., da Silva Lopes, C., da Costa e Silva, M.C., de Carvalho Sabino, K.C., Todeschini, A.R., Coelho, M.G. (2005). Antinociceptive properties of ethanolic extract and fractions of Pterodon pubescens Benth. seeds. Journal of Ethnopharmacology, 98(1-2):109 – 116. [CrossRef]
• 39. Pinheiro, M.M., Bessa, S.O., Fingolo, C.E., Kuster, R.M., Matheus, M.E., Menezes, F.S., Fernandes, P.D. (2010). Antinociceptive activity of fractions from Couroupita guianensis Aubl. leaves. Journal of Ethnopharmacology, 127(2), 407 – 413. [CrossRef]
• 40. Pinheiro, M.M., Boylan, F., Fernandes, P.D. (2012). Antinociceptive effect of the Orbignya speciosa Mart. (Babassu) leaves: evidence for the involvement of apigenin. Life Sciences, 91(9-10), 293 – 300. [CrossRef]
• 41. Millan, M.J. (2002). Descending control of pain. Progress in Neurobiology, 66(6):355 – 474. [CrossRef]
• 42. Argoff, C. (2011). Mechanisms of pain transmission and pharmacologic management. Current Medical Research and Opinion, 27(10), 2019 – 2031. [CrossRef]