Sari Youssef, Swiss Ghadeer M S, Alrashedi Fatin A, Baeshen Kholoud A, Alshammari Sultan A, Alsharari Shakir D, Ali Nemat, Alasmari Abdullah F, Alhoshani Ali, Alameen Alaa A, Childers Wayne E, Abou-Gharbia Magid, Alasmari Fawaz
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Saudi Pharm J. 2024 Jul;32(7):102108. doi: 10.1016/j.jsps.2024.102108. Epub 2024 May 23.
Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-β) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-β mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.
长期暴露于阿片类药物可导致星形胶质细胞谷氨酸转运体1（GLT-1）下调，而GLT-1可调节大部分谷氨酸的摄取。我们实验室的研究表明，β-内酰胺抗生素头孢曲松可减弱氢可酮诱导的GLT-1下调以及中枢奖赏脑区中胱氨酸/谷氨酸反向转运体（xCT）的表达。在本研究中，我们研究了递增剂量吗啡的作用，并测试了新型合成非抗生素药物MC-100093和头孢曲松在减轻吗啡暴露对伏隔核（NAc）中GLT-1、xCT和神经炎症因子（IL-6和TGF-β）表达影响方面的功效。本研究还研究了吗啡和β-内酰胺类药物对运动活动、自发交替百分比（SAP）和Y迷宫进入次数的影响，因为阿片类药物对运动致敏有影响。小鼠在第1、3、5、7天接受中等剂量吗啡（20mg/kg，腹腔注射），在第9天接受更高剂量吗啡（150mg/kg，腹腔注射），然后在第10天对这些小鼠进行行为测试并实施安乐死。蛋白质免疫印迹分析表明，暴露于吗啡会使NAc中GLT-1和xCT的表达下调，而MC-100093和头孢曲松均可减弱这些作用。此外，吗啡暴露会增加IL-6 mRNA和TGF-β mRNA的表达，但MC-100093和头孢曲松仅减弱对NAc中IL-6 mRNA表达的影响。此外，吗啡暴露会导致行进距离增加，而MC-100093和头孢曲松可减弱这种作用。另外，吗啡暴露会降低SAP并增加Y迷宫的臂进入次数，然而，MC-100093和头孢曲松均未显示出任何减弱作用。我们的研究结果首次证明，MC-100093和头孢曲松可减弱吗啡诱导的GLT-1和xCT表达下调，以及吗啡诱导的神经炎症因子IL-6增加和多动。这些发现揭示了MC-100093和头孢曲松对抗递增剂量吗啡暴露影响的有益治疗作用。
