抑制TRPM2阳离子通道通过调节内质网应激和细胞凋亡减弱吗啡耐受性。

IF 2.5 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters Pub Date : 2025-02-18 DOI:10.1016/j.neulet.2025.138168

Arzuhan Cetindag Ciltas , Ercan Ozdemir , Handan Gunes , Aysegul Ozturk

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引用次数: 0

摘要

阿片类药物，如吗啡，通常是治疗癌症和慢性疾病严重疼痛的首选药物，但长期使用会导致阿片类药物耐受。阿片类药物耐受性的机制非常复杂，尚未完全了解。本研究旨在探讨TRPM2阳离子通道拮抗剂N-（对氨基肉桂酰）邻氨基苯甲酸（ACA）和2-氨基乙氧基二苯硼酸酯（2-APB）对大鼠吗啡镇痛和耐受的影响。选取48只雄性Wistar Albino大鼠，随机分为药物组和对照组（生理盐水组）。为了诱导吗啡耐受，大鼠腹腔注射10 mg/kg吗啡，持续7 天。热镇痛试验后，分离背根神经节（DRG）和皮质组织。通过组织匀浆生化分析，检测促凋亡介质caspase-3和caspase- 9、总氧化状态（TOS）和总抗氧化状态（TAS）以及ER应激蛋白GRP78/BiP、ATF-6、p-IRE1和pERK水平。结果显示，给予ACA和2-APB的大鼠吗啡耐受性显著降低(p

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Inhibition of the TRPM2 cation channel attenuates morphine tolerance by modulating endoplasmic reticulum stress and apoptosis in rats

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Inhibition of the TRPM2 cation channel attenuates morphine tolerance by modulating endoplasmic reticulum stress and apoptosis in rats

Opioid drugs such as morphine are frequently preferred drugs for severe pain in cancer and chronic diseases, but long-term use causes opioid tolerance. The mechanism of tolerance to opioids is quite complex and not fully understood. Our aim in this study was to investigate the effects of TRPM2 cation channel antagonists N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethoxydiphenyl borate (2-APB) on morphine analgesia and tolerance in rats. Forty-eight Wistar Albino male rats were included in the study and the rats were randomly divided into drug and control (saline) groups. To induce morphine tolerance, the rats were injected with 10 mg/kg morphine intraperitoneally for 7 days. After thermal analgesia tests, dorsal root ganglion (DRG) and cortex tissues were isolated. Proapoptotic mediators caspase-3 and 9, total oxidant status (TOS) and total antioxidant status (TAS) and ER stress proteins GRP78/BiP, ATF-6, p-IRE1 and pERK levels were measured by biochemical analysis of tissue homogenates. The findings showed that there was a significant decrease in morphine tolerance in rats administered ACA and 2-APB (p<0.05). In addition, biochemical tests revealed a significant decrease in ER stress proteins, proapoptotic biomarkers and TOS levels and a significant increase in TAS levels in DRG, thalamus and sensory cortex tissues (p<0.05). In conclusion, inhibition of TRPM2 cation channel by ACA and 2-APB reduces morphine tolerance by preventing ER stress and apoptosis. It may be possible to increase the analgesic potential of morphine by combined application with ACA and 2-APB in the clinic, but further experimental and molecular studies are needed.

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来源期刊

Neuroscience Letters 医学-神经科学

CiteScore

5.20

自引率

0.00%

发文量

408

审稿时长

50 days

期刊介绍： Neuroscience Letters is devoted to the rapid publication of short, high-quality papers of interest to the broad community of neuroscientists. Only papers which will make a significant addition to the literature in the field will be published. Papers in all areas of neuroscience - molecular, cellular, developmental, systems, behavioral and cognitive, as well as computational - will be considered for publication. Submission of laboratory investigations that shed light on disease mechanisms is encouraged. Special Issues, edited by Guest Editors to cover new and rapidly-moving areas, will include invited mini-reviews. Occasional mini-reviews in especially timely areas will be considered for publication, without invitation, outside of Special Issues; these un-solicited mini-reviews can be submitted without invitation but must be of very high quality. Clinical studies will also be published if they provide new information about organization or actions of the nervous system, or provide new insights into the neurobiology of disease. NSL does not publish case reports.