Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice
Morphine belongs to the class of opioids and is known for its potential to cause dependence and addiction, particularly with prolonged use. Due to the associated risks, caution must be taken when prescribing and limiting its clinical use. Overexpression of N-methyl-D-aspartate (NMDA) receptors, nitr...
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Elsevier
2024-12-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024166157 |
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| author | Shabir Hussain Haji Bahadar Muhammad Imran Khan Neelum Gul Qazi Shabnum Gul Wazir Habab Ali Ahmad |
| author_facet | Shabir Hussain Haji Bahadar Muhammad Imran Khan Neelum Gul Qazi Shabnum Gul Wazir Habab Ali Ahmad |
| author_sort | Shabir Hussain |
| collection | DOAJ |
| description | Morphine belongs to the class of opioids and is known for its potential to cause dependence and addiction, particularly with prolonged use. Due to the associated risks, caution must be taken when prescribing and limiting its clinical use. Overexpression of N-methyl-D-aspartate (NMDA) receptors, nitric oxide and cGMP pathway has been implicated in exacerbate the development of morphine dependence and withdrawal. Topiramate, an antiepileptic drug, interacts with various receptors, ion channels and certain enzymes. In this study, we investigated the effects of topiramate on morphine dependence in mice, specifically targeting NMDA/Nitric oxide/cGMP pathway. Mice were administered different doses of topiramate (intraperitoneally) during the development phase, 45 min prior to morphine administration. Topiramate (20 mg/kg) significantly reduced naloxone-induced withdrawal symptoms in morphine-dependent mice. Additionally, subeffective doses of topiramate, when co-administered with NMDA receptor antagonist MK-801 (0.05 mg/kg) or nitric oxide synthase inhibitors such as L-NAME (10 mg/kg, a non-specific NOS inhibitor) and 7-NI (20 mg/kg, a selective nNOS inhibitor), showed a marked reduction in withdrawal signs. However, the effect of topiramate (20 mg/kg) was abolished when co-administered with NMDA (75 mg/kg, an NMDA receptor agonist) or L-arginine (60 mg/kg, a NOS substrate). Ex-vivo analysis revealed that topiramate significantly reduced oxidative stress and downregulated the gene expression of nNOS, NR1, and NR2B in morphine-treated mice. Furthermore, the expression of NR1 and NR2B proteins in the hippocampus and cortex was significantly reduced in topiramate-pretreated mice. Hence, this finding suggest that topiramate mitigates morphine dependence and withdrawal by inhibiting oxidative stress and modulating the NMDA/NO pathway. |
| format | Article |
| id | doaj-art-32b424b59f1b48289c633a13f7a06d95 |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-32b424b59f1b48289c633a13f7a06d952024-12-13T10:59:09ZengElsevierHeliyon2405-84402024-12-011023e40584Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in miceShabir Hussain0Haji Bahadar1Muhammad Imran Khan2Neelum Gul Qazi3Shabnum Gul Wazir4Habab Ali Ahmad5Department of Pharmacology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa, PakistanDepartment of Pharmacology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa, Pakistan; Institute of Pharmaceutical Sciences, Khyber Medical University, Khyber Pakhtunkhwa, Pakistan; Corresponding author. Institute of Pharmaceutical Sciences, Khyber Medical University, Khyber Pakhtunkhwa, Pakistan.Department of Biomedical Sciences, Pak Austria Fachhochschule: Institute of Applied Sciences and Technology, Haripur, Khyber Pakhtunkhwa, Pakistan; Corresponding author. Department of Biomedical Sciences, Pak Austria Fachhochschule: IAST, Haripur, Khyber Pakhtunkhwa, Pakistan.Department of Pharmacy, Iqra University, Islamabad, PakistanFrontier Medical and Dental College, Abbottabad, Khyber Pakhtunkhwa, PakistanDepartment of Biomedical Sciences, Pak Austria Fachhochschule: Institute of Applied Sciences and Technology, Haripur, Khyber Pakhtunkhwa, PakistanMorphine belongs to the class of opioids and is known for its potential to cause dependence and addiction, particularly with prolonged use. Due to the associated risks, caution must be taken when prescribing and limiting its clinical use. Overexpression of N-methyl-D-aspartate (NMDA) receptors, nitric oxide and cGMP pathway has been implicated in exacerbate the development of morphine dependence and withdrawal. Topiramate, an antiepileptic drug, interacts with various receptors, ion channels and certain enzymes. In this study, we investigated the effects of topiramate on morphine dependence in mice, specifically targeting NMDA/Nitric oxide/cGMP pathway. Mice were administered different doses of topiramate (intraperitoneally) during the development phase, 45 min prior to morphine administration. Topiramate (20 mg/kg) significantly reduced naloxone-induced withdrawal symptoms in morphine-dependent mice. Additionally, subeffective doses of topiramate, when co-administered with NMDA receptor antagonist MK-801 (0.05 mg/kg) or nitric oxide synthase inhibitors such as L-NAME (10 mg/kg, a non-specific NOS inhibitor) and 7-NI (20 mg/kg, a selective nNOS inhibitor), showed a marked reduction in withdrawal signs. However, the effect of topiramate (20 mg/kg) was abolished when co-administered with NMDA (75 mg/kg, an NMDA receptor agonist) or L-arginine (60 mg/kg, a NOS substrate). Ex-vivo analysis revealed that topiramate significantly reduced oxidative stress and downregulated the gene expression of nNOS, NR1, and NR2B in morphine-treated mice. Furthermore, the expression of NR1 and NR2B proteins in the hippocampus and cortex was significantly reduced in topiramate-pretreated mice. Hence, this finding suggest that topiramate mitigates morphine dependence and withdrawal by inhibiting oxidative stress and modulating the NMDA/NO pathway.http://www.sciencedirect.com/science/article/pii/S2405844024166157MorphineNMDANitric oxideMK-801DependenceOxidative stress |
| spellingShingle | Shabir Hussain Haji Bahadar Muhammad Imran Khan Neelum Gul Qazi Shabnum Gul Wazir Habab Ali Ahmad Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice Heliyon Morphine NMDA Nitric oxide MK-801 Dependence Oxidative stress |
| title | Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| title_full | Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| title_fullStr | Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| title_full_unstemmed | Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| title_short | Modulation of oxidative stress/NMDA/nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| title_sort | modulation of oxidative stress nmda nitric oxide pathway by topiramate attenuates morphine dependence in mice |
| topic | Morphine NMDA Nitric oxide MK-801 Dependence Oxidative stress |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024166157 |
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