Hussain Shabir, Bahadar Haji, Khan Muhammad Imran, Qazi Neelum Gul, Wazir Shabnum Gul, Ahmad Habab Ali
Department of Pharmacology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa, Pakistan.
Institute of Pharmaceutical Sciences, Khyber Medical University, Khyber Pakhtunkhwa, Pakistan.
Heliyon. 2024 Nov 22;10(23):e40584. doi: 10.1016/j.heliyon.2024.e40584. eCollection 2024 Dec 15.
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). 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.
吗啡属于阿片类药物，因其具有导致依赖和成瘾的可能性而闻名，尤其是长期使用时。由于存在相关风险，在开具处方和限制其临床使用时必须谨慎。N-甲基-D-天冬氨酸（NMDA）受体、一氧化氮和环磷酸鸟苷（cGMP）途径的过表达与吗啡依赖和戒断的发展加剧有关。托吡酯是一种抗癫痫药物，可与多种受体、离子通道和某些酶相互作用。在本研究中，我们研究了托吡酯对小鼠吗啡依赖的影响，特别针对NMDA/一氧化氮/cGMP途径。在吗啡给药前45分钟的发育阶段，给小鼠腹腔注射不同剂量的托吡酯。托吡酯（20毫克/千克）显著减轻了吗啡依赖小鼠中纳洛酮诱导的戒断症状。此外，当亚有效剂量的托吡酯与NMDA受体拮抗剂MK-801（0.05毫克/千克）或一氧化氮合酶抑制剂如L- NAME（10毫克/千克，一种非特异性一氧化氮合酶抑制剂）和7-NI（20毫克/千克，一种选择性神经元型一氧化氮合酶抑制剂）共同给药时，戒断症状明显减轻。然而，当与NMDA（75毫克/千克，一种NMDA受体激动剂）或L-精氨酸（60毫克/千克，一种一氧化氮合酶底物）共同给药时，托吡酯（20毫克/千克）的作用被消除。分析表明，托吡酯显著降低了氧化应激，并下调了吗啡处理小鼠中神经元型一氧化氮合酶、NR1和NR2B的基因表达。此外，在托吡酯预处理的小鼠中，海马体和皮质中NR1和NR2B蛋白的表达显著降低。因此，这一发现表明托吡酯通过抑制氧化应激和调节NMDA/一氧化氮途径来减轻吗啡依赖和戒断。
