Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways
Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking stu...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223008594 |
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| author | Asser F. Bedair Ahmed Wahid Nesrine S. El-Mezayen Amira F. El-Yazbi Hadeel A. Khalil Nayera W. Hassan Elham A. Afify |
| author_facet | Asser F. Bedair Ahmed Wahid Nesrine S. El-Mezayen Amira F. El-Yazbi Hadeel A. Khalil Nayera W. Hassan Elham A. Afify |
| author_sort | Asser F. Bedair |
| collection | DOAJ |
| description | Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking studies. Male Wistar rats were injected intraperitoneally (i.p.) with carbon tetrachloride (CCl4, 40%, 2 ml/kg) twice weekly for 5 weeks to induce hepatic fibrosis. Nicorandil (15 mg/kg/day) was administered per os (p.o.) for 14 days in presence of the blockers; glibenclamide (KATP channel blocker, 5 mg/kg, p.o.), L-NG-nitro-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 15 mg/kg, p.o.), methylene blue (MB, guanylyl cyclase inhibitor, 2 mg/kg, i.p.) and naltrexone (opioid antagonist, 20 mg/kg, i.p.). At the end of the 5th week, analgesia was evaluated using tail flick and formalin tests along with biochemical determinations of liver function tests, oxidative stress markers and histopathological examination of liver tissues. Naltrexone and MB inhibited the antinociceptive activity of the combination. Furthermore, combined nicorandil/morphine regimen attenuated the release of endogenous peptides. Docking studies revealed a possible interaction of nicorandil on µ, κ and δ opioid receptors. Nicorandil/morphine combination protected against liver damage as evident by decreased liver enzymes, liver index, hyaluronic acid, lipid peroxidation, fibrotic insults, and increased superoxide dismutase activity. Nicorandil/morphine hepatoprotection and antioxidant activity were inhibited by glibenclamide and L-NAME but not by naltrexone or MB. These findings implicate opioid activation/cGMP versus NO/KATP channels in the augmented antinociception, and hepatoprotection, respectively, of the combined therapy and implicate provoked cross talk by nicorandil and morphine on opioid receptors and cGMP signaling pathway. That said, nicorandil/morphine combination provides a potential multitargeted therapy to alleviate pain and preserve liver function. |
| first_indexed | 2024-03-12T15:05:49Z |
| format | Article |
| id | doaj.art-e3d2a76c92a744a7a4345e7b02192198 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-12T15:05:49Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-e3d2a76c92a744a7a4345e7b021921982023-08-13T04:52:28ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-09-01165115068Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathwaysAsser F. Bedair0Ahmed Wahid1Nesrine S. El-Mezayen2Amira F. El-Yazbi3Hadeel A. Khalil4Nayera W. Hassan5Elham A. Afify6Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Alexandria, Alexandria, EgyptDepartment of Pharmaceutical Biochemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, EgyptDepartment of Pharmacology, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, EgyptDepartment of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, EgyptDepartment of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt; Correspondence to: 1-el-Khartoum square-Azarita, postal code: 21521, Alexandria, Egypt.Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking studies. Male Wistar rats were injected intraperitoneally (i.p.) with carbon tetrachloride (CCl4, 40%, 2 ml/kg) twice weekly for 5 weeks to induce hepatic fibrosis. Nicorandil (15 mg/kg/day) was administered per os (p.o.) for 14 days in presence of the blockers; glibenclamide (KATP channel blocker, 5 mg/kg, p.o.), L-NG-nitro-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 15 mg/kg, p.o.), methylene blue (MB, guanylyl cyclase inhibitor, 2 mg/kg, i.p.) and naltrexone (opioid antagonist, 20 mg/kg, i.p.). At the end of the 5th week, analgesia was evaluated using tail flick and formalin tests along with biochemical determinations of liver function tests, oxidative stress markers and histopathological examination of liver tissues. Naltrexone and MB inhibited the antinociceptive activity of the combination. Furthermore, combined nicorandil/morphine regimen attenuated the release of endogenous peptides. Docking studies revealed a possible interaction of nicorandil on µ, κ and δ opioid receptors. Nicorandil/morphine combination protected against liver damage as evident by decreased liver enzymes, liver index, hyaluronic acid, lipid peroxidation, fibrotic insults, and increased superoxide dismutase activity. Nicorandil/morphine hepatoprotection and antioxidant activity were inhibited by glibenclamide and L-NAME but not by naltrexone or MB. These findings implicate opioid activation/cGMP versus NO/KATP channels in the augmented antinociception, and hepatoprotection, respectively, of the combined therapy and implicate provoked cross talk by nicorandil and morphine on opioid receptors and cGMP signaling pathway. That said, nicorandil/morphine combination provides a potential multitargeted therapy to alleviate pain and preserve liver function.http://www.sciencedirect.com/science/article/pii/S0753332223008594Nitric oxideOpioidergicKATP channels, liver fibrosis |
| spellingShingle | Asser F. Bedair Ahmed Wahid Nesrine S. El-Mezayen Amira F. El-Yazbi Hadeel A. Khalil Nayera W. Hassan Elham A. Afify Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways Biomedicine & Pharmacotherapy Nitric oxide Opioidergic KATP channels, liver fibrosis |
| title | Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways |
| title_full | Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways |
| title_fullStr | Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways |
| title_full_unstemmed | Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways |
| title_short | Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways |
| title_sort | nicorandil morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats distinct roles of opioid cgmp and no katp pathways |
| topic | Nitric oxide Opioidergic KATP channels, liver fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223008594 |
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