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Protective effect of telmisartan against morphine-induced analgesic tolerance in mice

Yıl 2024, Cilt: 28 Sayı: 4, 1079 - 1087, 28.06.2025

Elif Nur Barut , Seçkin Engin , Yeşim Kaya Yaşar , Elif Gun Mine Duman

Öz

Morphine tolerance is a serious clinical problem characterized by a decreased analgesic effect resulted from the long-term use of morphine with uncertain etiology and therapeutic interventions are limited. In this study, we aimed to investigate the effect of telmisartan in a mouse model of morphine-induced analgesic tolerance and the underlying mechanisms of its action. Morphine (10 mg/kg) was injected subcutaneously twice daily for five days. Mice were pretreated with Telmisartan (TEL; 5 and 15 mg/kg) orally by gavage 30 min before each morphine injection. L-NAME (10 mg/kg), L-arginine (L-ARG,300 mg/kg) or N-acetylcysteine (NAC, 50 mg/kg) was administered intraperitoneally 45 min prior to morphine. Analgesic efficacy was evaluated by hot-plate test on 1st, 3rd and 5th days, 60 min after morphine injection. Spinal cord samples of mice were used to examine the protein expressions of nNOS and iNOS by western blotting and total GSH content. Repeated morphine administration caused a significant decrease in analgesic efficacy, demonstrating the development of morphine tolerance. High-dose TEL treatment effectively prevented morphine-induced analgesic tolerance. L-ARG abolished the inhibitory effect of TEL on morphine tolerance, while L- NAME and NAC did not alter. GSH level and nNOS expression were decreased, as well as iNOS expression was increased in the spinal cords from morphine-tolerant mice. TEL (15 mg/kg) treatment prevented the decrease in GSH level and the increase in iNOS expression of spinal cords. TEL would be a potential therapeutic candidate in preventing morphine tolerance through its activity on antioxidant systems and, in part, on the nitric oxide pathway.

Anahtar Kelimeler

hot-plate test mice morphine tolerance nitric oxide telmisartan

Kaynakça

  • [1] Skrabalova J, Drastichova Z, Novotny J. Morphine as a potential oxidative stress-causing agent. Mini Rev Org Chem. 2013;10(4):367-372. http://doi.org/10.2174/1570193X113106660031
  • [2] Mansouri MT, Naghizadeh B, Ghorbanzadeh B, Alboghobeish S, Amirgholami N, Houshmand G, Cauli O. oxide Venlafaxine prevents morphine antinociceptive tolerance: The role of neuroinflammation and the l-arginine-nitric pathway. Exp Neurol. 2018;303:134-141. http://doi.org/10.1016/j.expneurol.2018.02.009
  • [3] de Guglielmo G, Kallupi M, Scuppa G, Stopponi S, Demopulos G, Gaitanaris G, Ciccocioppo R. Analgesic tolerance to morphine is regulated by PPARγ. Br J Pharmacol. 2014;171(23):5407-5416. http://doi.org/10.1111/bph.12851
  • [4] Fatemi I, Amirteimoury M, Shamsizadeh A, Kaeidi A. The effect of metformin on morphine analgesic tolerance and dependence in rats. Res Pharm Sci. 2018;13(4):316-323. http://doi.org/10.4103/1735-5362.235158
  • [5] Xin W, Chun W, Ling L, Wei W. Role of melatonin in the prevention of morphine-induced hyperalgesia and spinal glial activation in rats: protein kinase C pathway involved. Int J Neurosci. 2012;122(3):154-163. http://doi.org/10.3109/00207454.2011.635828
  • [6] Zhang YT, Zheng QS, Pan J, Zheng RL. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol. 2004;95(2):53-58. http://doi.org/10.1111/j.1742-7843.2004.950202.x
  • [7] Payabvash S, Beheshtian A, Salmasi AH, Kiumehr S, Ghahremani MH, Tavangar SM, Sabzevari O, Dehpour AR. Chronic morphine treatment induces oxidant and apoptotic damage in the mice liver. Life Sci. 2006;79(10):972-980. http://doi.org/10.1016/j.lfs.2006.05.008
  • [8] Goudas LC, Langlade A, Serrie A, Matson W, Milbury P, Thurel C, Sandouk P, Carr DB. Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain. Anesth Analg. 1999;89(5):1209-1215. http://doi.org/10.1213/00000539-199911000-00023
  • [9] Abdel-Zaher AO, Hamdy MM, Aly SA, Abdel-Hady RH, Abdel-Rahman S. Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol. 2006;540(1-3):60-66. http://doi.org/10.1016/j.ejphar.2006.03.059
  • [10] Abdel-Zaher AO, Mostafa MG, Farghaly HS, Hamdy MM, Abdel-Hady RH. Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav Brain Res. 2013;247:17-26. http://doi.org/10.1016/j.bbr.2013.02.034
  • [11] Dambisya YM, Lee TL. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice. Br J Pharmacol.1996;117(5):914-918. http://doi.org/10.1111/j.1476-5381.1996.tb15280.x
  • [12] Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology.1994; 33(11):1463-1470. http://doi.org/10.1016/0028-3908(94)90050-7
  • [13] Ozdemir E, Bagcivan I, Durmus N, Altun A, Gursoy S. The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine. Can J Physiol Pharmacol. 2011; 89(2):89-95. http://doi.org/10.1139/y10-109
  • [14] Yin SN, Liu M, Jing DQ, Mu YM, Lu JM, Pan CY. Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells. Endocr Res. 2014;39(2):66-72. http://doi.org/10.3109/07435800.2013.828741
  • [15] Eslami H, Sharifi AM, Rahimi H, Rahati M. Protective effect of telmisartan against oxidative damage induced by high glucose in neuronal PC12 cell. Neurosci Lett. 2014;558:31-36. http://doi.org/10.1016/j.neulet.2013.10.057
  • [16] Yoo SM, Choi SH, Jung MD, Lim SC, Baek SH. Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant β-blockers in the cardiovascular systems of spontaneously hypertensive rats. Hypertens Res. 2015;38(2):106-115. http://doi.org/10.1038/hr.2014.151
  • [17] Yuen CY, Wong WT, Tian XY, Wong SL, Lau CW, Yu J, Tomlinson B, Yao X, Huang Y. Telmisartan inhibits vasoconstriction via PPARγ-dependent expression and activation of endothelial nitric oxide synthase. Cardiovasc Res. 2011;90(1):122-129. http://doi.org/10.1093/cvr/cvq392
  • [18] Kumtepe Y, Odabasoglu F, Karaca M, Polat B, Halici MB, Keles ON, Altunkaynak Z, Gocer F. Protective effects of telmisartan on ischemia/reperfusion injury of rat ovary: biochemical and histopathologic evaluation. Fertil Steril. 2010;93(4):1299-1307. http://doi.org/10.1016/j.fertnstert.2008.12.016
  • [19] Xu Y, Xu Y, Wang Y, Wang Y, He L, Jiang Z, Huang Z, Liao H, Li J, Saavedra JM, Zhang L, Pang T. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun. 2015;50:298-313. http://doi.org/10.1016/j.bbi.2015.07.015
  • [20] Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan modulates glial activation: In vitro and ın vivo studies. PLoS One. 2016;11(5):e0155823. http://doi.org/10.1371/journal.pone.0155823
  • [21] Karádi DÁ, Galambos AR, Lakatos PP, Apenberg J, Abbood SK, Balogh M, Király K, Riba P, Essmat N, Szűcs E, Benyhe S, Varga ZV, Szökő É, Tábi T, Al-Khrasani M. Telmisartan ıs a promising agent for managing neuropathic pain and delaying opioid analgesic tolerance in rats. Int J Mol Sci. 2023;24(9):7970. http://doi.org/10.3390/ijms24097970
  • [22] Motaghinejad M, Karimian SM, Motaghinejad O, Shabab B, Asadighaleni M, Fatima S. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats. Fundam Clin Pharmacol. 2015;29(3):299-309. http://doi.org/10.1111/fcp.12121
  • [23] Salvemini D, Neumann WL. Peroxynitrite: a strategic linchpin of opioid analgesic tolerance. Trends Pharmacol Sci. 2009;30(4):194-202. http://doi.org/10.1016/j.tips.2008.12.005
  • [24] Zeng XS, Geng WS, Wang ZQ, Jia JJ. Morphine addiction and oxidative stress: The potential effects of thioredoxin-1. Front Pharmacol. 2020;11:82. http://doi.org/10.3389/fphar.2020.00082
  • [25] Trivedi M, Shah J, Hodgson N, Byun HM, Deth R. Morphine induces redox-based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake. Mol Pharmacol. 2014;85(5):747-757. http://doi.org/10.1124/mol.114.091728
  • [26] Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules. 2018;23(12):3305. http://doi.org/10.3390/molecules23123305
  • [27] Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain. 1994;56(1):69-75. http://doi.org/10.1016/0304-3959(94)90151-1
  • [28] Majeed NH, Przewłocka B, Machelska H, Przewłocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology. 1994;33(2):189-192. http://doi.org/10.1016/0028-3908(94)90006-x
  • [29] Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol. 2004;67(4):735-741. http://doi.org/10.1016/j.bcp.2003.08.046
  • [30] Naidu PS, Singh A, Joshi D, Kulkarni SK. Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence. Addict Biol. 2003;8(3):327-336. http://doi.org/10.1080/13556210310001602248
  • [31] Khan MI, Ostadhadi S, Mumtaz F, Momeny M, Moghaddaskho F, Hassanipour M, Ejtemaei-Mehr S, Dehpour AR. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway. Biomed Pharmacother. 2017;85:493-502. http://doi.org/10.1016/j.biopha.2016.11.056
  • [32] Lipták N, Dochnal R, Csabafi K, Szakács J, Szabó G. Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice. Regul Pept. 2013;186:77-82. http://doi.org/10.1016/j.regpep.2013.07.006
  • [33] Engin S, Barut EN, Yaşar YK, Soysal AÇ, Arıcı T, Kerimoğlu G, Kadıoğlu M, Sezen SF. Trimetazidine attenuates cyclophosphamide-induced cystitis by inhibiting TLR4-mediated NFκB signaling in mice. Life Sci. 2022;301:120590. http://doi.org/10.1016/j.lfs.2022.120590
  • [34] Barut B, Yalçın CÖ, Altun Y, Akkaya D, Barut EN, Baş H, Bıyıklıoğlu Z. Evaluation of photodynamic therapy effects of novel zinc (II) phthalocyanine through a possible interaction with toll-like receptor signaling pathway. Appl Organomet Chem. 2023;37(4): e7039. https://doi.org/10.1002/aoc.7039

Yıl 2024, Cilt: 28 Sayı: 4, 1079 - 1087, 28.06.2025

Elif Nur Barut , Seçkin Engin , Yeşim Kaya Yaşar , Elif Gun Mine Duman

Öz

Kaynakça

  • [1] Skrabalova J, Drastichova Z, Novotny J. Morphine as a potential oxidative stress-causing agent. Mini Rev Org Chem. 2013;10(4):367-372. http://doi.org/10.2174/1570193X113106660031
  • [2] Mansouri MT, Naghizadeh B, Ghorbanzadeh B, Alboghobeish S, Amirgholami N, Houshmand G, Cauli O. oxide Venlafaxine prevents morphine antinociceptive tolerance: The role of neuroinflammation and the l-arginine-nitric pathway. Exp Neurol. 2018;303:134-141. http://doi.org/10.1016/j.expneurol.2018.02.009
  • [3] de Guglielmo G, Kallupi M, Scuppa G, Stopponi S, Demopulos G, Gaitanaris G, Ciccocioppo R. Analgesic tolerance to morphine is regulated by PPARγ. Br J Pharmacol. 2014;171(23):5407-5416. http://doi.org/10.1111/bph.12851
  • [4] Fatemi I, Amirteimoury M, Shamsizadeh A, Kaeidi A. The effect of metformin on morphine analgesic tolerance and dependence in rats. Res Pharm Sci. 2018;13(4):316-323. http://doi.org/10.4103/1735-5362.235158
  • [5] Xin W, Chun W, Ling L, Wei W. Role of melatonin in the prevention of morphine-induced hyperalgesia and spinal glial activation in rats: protein kinase C pathway involved. Int J Neurosci. 2012;122(3):154-163. http://doi.org/10.3109/00207454.2011.635828
  • [6] Zhang YT, Zheng QS, Pan J, Zheng RL. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol. 2004;95(2):53-58. http://doi.org/10.1111/j.1742-7843.2004.950202.x
  • [7] Payabvash S, Beheshtian A, Salmasi AH, Kiumehr S, Ghahremani MH, Tavangar SM, Sabzevari O, Dehpour AR. Chronic morphine treatment induces oxidant and apoptotic damage in the mice liver. Life Sci. 2006;79(10):972-980. http://doi.org/10.1016/j.lfs.2006.05.008
  • [8] Goudas LC, Langlade A, Serrie A, Matson W, Milbury P, Thurel C, Sandouk P, Carr DB. Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain. Anesth Analg. 1999;89(5):1209-1215. http://doi.org/10.1213/00000539-199911000-00023
  • [9] Abdel-Zaher AO, Hamdy MM, Aly SA, Abdel-Hady RH, Abdel-Rahman S. Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol. 2006;540(1-3):60-66. http://doi.org/10.1016/j.ejphar.2006.03.059
  • [10] Abdel-Zaher AO, Mostafa MG, Farghaly HS, Hamdy MM, Abdel-Hady RH. Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav Brain Res. 2013;247:17-26. http://doi.org/10.1016/j.bbr.2013.02.034
  • [11] Dambisya YM, Lee TL. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice. Br J Pharmacol.1996;117(5):914-918. http://doi.org/10.1111/j.1476-5381.1996.tb15280.x
  • [12] Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology.1994; 33(11):1463-1470. http://doi.org/10.1016/0028-3908(94)90050-7
  • [13] Ozdemir E, Bagcivan I, Durmus N, Altun A, Gursoy S. The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine. Can J Physiol Pharmacol. 2011; 89(2):89-95. http://doi.org/10.1139/y10-109
  • [14] Yin SN, Liu M, Jing DQ, Mu YM, Lu JM, Pan CY. Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells. Endocr Res. 2014;39(2):66-72. http://doi.org/10.3109/07435800.2013.828741
  • [15] Eslami H, Sharifi AM, Rahimi H, Rahati M. Protective effect of telmisartan against oxidative damage induced by high glucose in neuronal PC12 cell. Neurosci Lett. 2014;558:31-36. http://doi.org/10.1016/j.neulet.2013.10.057
  • [16] Yoo SM, Choi SH, Jung MD, Lim SC, Baek SH. Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant β-blockers in the cardiovascular systems of spontaneously hypertensive rats. Hypertens Res. 2015;38(2):106-115. http://doi.org/10.1038/hr.2014.151
  • [17] Yuen CY, Wong WT, Tian XY, Wong SL, Lau CW, Yu J, Tomlinson B, Yao X, Huang Y. Telmisartan inhibits vasoconstriction via PPARγ-dependent expression and activation of endothelial nitric oxide synthase. Cardiovasc Res. 2011;90(1):122-129. http://doi.org/10.1093/cvr/cvq392
  • [18] Kumtepe Y, Odabasoglu F, Karaca M, Polat B, Halici MB, Keles ON, Altunkaynak Z, Gocer F. Protective effects of telmisartan on ischemia/reperfusion injury of rat ovary: biochemical and histopathologic evaluation. Fertil Steril. 2010;93(4):1299-1307. http://doi.org/10.1016/j.fertnstert.2008.12.016
  • [19] Xu Y, Xu Y, Wang Y, Wang Y, He L, Jiang Z, Huang Z, Liao H, Li J, Saavedra JM, Zhang L, Pang T. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun. 2015;50:298-313. http://doi.org/10.1016/j.bbi.2015.07.015
  • [20] Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan modulates glial activation: In vitro and ın vivo studies. PLoS One. 2016;11(5):e0155823. http://doi.org/10.1371/journal.pone.0155823
  • [21] Karádi DÁ, Galambos AR, Lakatos PP, Apenberg J, Abbood SK, Balogh M, Király K, Riba P, Essmat N, Szűcs E, Benyhe S, Varga ZV, Szökő É, Tábi T, Al-Khrasani M. Telmisartan ıs a promising agent for managing neuropathic pain and delaying opioid analgesic tolerance in rats. Int J Mol Sci. 2023;24(9):7970. http://doi.org/10.3390/ijms24097970
  • [22] Motaghinejad M, Karimian SM, Motaghinejad O, Shabab B, Asadighaleni M, Fatima S. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats. Fundam Clin Pharmacol. 2015;29(3):299-309. http://doi.org/10.1111/fcp.12121
  • [23] Salvemini D, Neumann WL. Peroxynitrite: a strategic linchpin of opioid analgesic tolerance. Trends Pharmacol Sci. 2009;30(4):194-202. http://doi.org/10.1016/j.tips.2008.12.005
  • [24] Zeng XS, Geng WS, Wang ZQ, Jia JJ. Morphine addiction and oxidative stress: The potential effects of thioredoxin-1. Front Pharmacol. 2020;11:82. http://doi.org/10.3389/fphar.2020.00082
  • [25] Trivedi M, Shah J, Hodgson N, Byun HM, Deth R. Morphine induces redox-based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake. Mol Pharmacol. 2014;85(5):747-757. http://doi.org/10.1124/mol.114.091728
  • [26] Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules. 2018;23(12):3305. http://doi.org/10.3390/molecules23123305
  • [27] Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain. 1994;56(1):69-75. http://doi.org/10.1016/0304-3959(94)90151-1
  • [28] Majeed NH, Przewłocka B, Machelska H, Przewłocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology. 1994;33(2):189-192. http://doi.org/10.1016/0028-3908(94)90006-x
  • [29] Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol. 2004;67(4):735-741. http://doi.org/10.1016/j.bcp.2003.08.046
  • [30] Naidu PS, Singh A, Joshi D, Kulkarni SK. Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence. Addict Biol. 2003;8(3):327-336. http://doi.org/10.1080/13556210310001602248
  • [31] Khan MI, Ostadhadi S, Mumtaz F, Momeny M, Moghaddaskho F, Hassanipour M, Ejtemaei-Mehr S, Dehpour AR. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway. Biomed Pharmacother. 2017;85:493-502. http://doi.org/10.1016/j.biopha.2016.11.056
  • [32] Lipták N, Dochnal R, Csabafi K, Szakács J, Szabó G. Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice. Regul Pept. 2013;186:77-82. http://doi.org/10.1016/j.regpep.2013.07.006
  • [33] Engin S, Barut EN, Yaşar YK, Soysal AÇ, Arıcı T, Kerimoğlu G, Kadıoğlu M, Sezen SF. Trimetazidine attenuates cyclophosphamide-induced cystitis by inhibiting TLR4-mediated NFκB signaling in mice. Life Sci. 2022;301:120590. http://doi.org/10.1016/j.lfs.2022.120590
  • [34] Barut B, Yalçın CÖ, Altun Y, Akkaya D, Barut EN, Baş H, Bıyıklıoğlu Z. Evaluation of photodynamic therapy effects of novel zinc (II) phthalocyanine through a possible interaction with toll-like receptor signaling pathway. Appl Organomet Chem. 2023;37(4): e7039. https://doi.org/10.1002/aoc.7039
Toplam 34 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Temel Farmakoloji
Bölüm Articles
Yazarlar

Elif Nur Barut 0000-0003-3284-848X

Seçkin Engin 0000-0002-1982-7820

Yeşim Kaya Yaşar 0000-0002-9938-3288

Elif Gun 0000-0003-4854-3701

Mine Duman 0000-0002-9057-0634

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2024 Cilt: 28 Sayı: 4

Kaynak Göster

APA Barut, E. N., Engin, S., Kaya Yaşar, Y., Gun, E., vd. (2025). Protective effect of telmisartan against morphine-induced analgesic tolerance in mice. Journal of Research in Pharmacy, 28(4), 1079-1087.
AMA Barut EN, Engin S, Kaya Yaşar Y, Gun E, Duman M. Protective effect of telmisartan against morphine-induced analgesic tolerance in mice. J. Res. Pharm. Temmuz 2025;28(4):1079-1087.
Chicago Barut, Elif Nur, Seçkin Engin, Yeşim Kaya Yaşar, Elif Gun, ve Mine Duman. “Protective Effect of Telmisartan Against Morphine-Induced Analgesic Tolerance in Mice”. Journal of Research in Pharmacy 28, sy. 4 (Temmuz 2025): 1079-87.
EndNote Barut EN, Engin S, Kaya Yaşar Y, Gun E, Duman M (01 Temmuz 2025) Protective effect of telmisartan against morphine-induced analgesic tolerance in mice. Journal of Research in Pharmacy 28 4 1079–1087.
IEEE E. N. Barut, S. Engin, Y. Kaya Yaşar, E. Gun, ve M. Duman, “Protective effect of telmisartan against morphine-induced analgesic tolerance in mice”, J. Res. Pharm., c. 28, sy. 4, ss. 1079–1087, 2025.
ISNAD Barut, Elif Nur vd. “Protective Effect of Telmisartan Against Morphine-Induced Analgesic Tolerance in Mice”. Journal of Research in Pharmacy 28/4 (Temmuz 2025), 1079-1087.
JAMA Barut EN, Engin S, Kaya Yaşar Y, Gun E, Duman M. Protective effect of telmisartan against morphine-induced analgesic tolerance in mice. J. Res. Pharm. 2025;28:1079–1087.
MLA Barut, Elif Nur vd. “Protective Effect of Telmisartan Against Morphine-Induced Analgesic Tolerance in Mice”. Journal of Research in Pharmacy, c. 28, sy. 4, 2025, ss. 1079-87.
Vancouver Barut EN, Engin S, Kaya Yaşar Y, Gun E, Duman M. Protective effect of telmisartan against morphine-induced analgesic tolerance in mice. J. Res. Pharm. 2025;28(4):1079-87.