N-methyl-d-aspartate receptor (NMDA-R)/nitric oxide (NO) pathway is involved in the intensification of the analgesic effect of opioids and the reduction of the intensity of opioids tolerance and dependence. In the current study, we investigated the involvement of NMDA-R/NO pathway in chronic morphine-treated mice in both the development of tolerance to the analgesic effect of morphine and in pentylenetetrazole (PTZ)-induced seizure threshold. Chronic treatment with morphine (30 mg/kg) exhibited increased seizure resistance in morphine-induced tolerant mice. The development of morphine tolerance was withdrawn when used concomitantly with NOS inhibitors and NMDA-R antagonist, suggesting that the development of tolerance to the anticonvulsant effect of morphine (30 mg/kg) is mediated through the NMDA-R/NO pathway. A dose-dependent biphasic seizure modulation of morphine was demonstrated in the acute treatment with morphine; acute treatment at a dose of 0.5 mg/kg shows the anticonvulsant effect and at a dose of 30 mg/kg shows proconvulsant effect. However, a different pattern was observed in the mice treated chronically with morphine: they demonstrated tolerance in the tail-flick test; five consecutive days of chronic treatment with a high dose of morphine (30 mg/kg) showed anticonvulsant effect while a low dose of morphine (0.5 mg/kg) showed a proconvulsant effect. The anticonvulsant effect of morphine was inhibited completely by the concomitant administration of NO synthase (NOS) inhibitors including nonspecific NOS inhibitor (L-NAME, 10 mg/kg), inducible NOS inhibitor (aminoguanidine, 50 mg/kg), and neuronal NOS inhibitor (7-nitroindazole (7-NI), 15 mg/kg) for five consecutive days. Besides, five days injection of NMDA-R antagonist (MK-801, 0.05 mg/kg) significantly inhibited the anticonvulsant effect of morphine on the PTZ-induced clonic seizures. The results revealed that chronic treatment with morphine leads to the development of tolerance in mice, which in turn may cause an anticonvulsant effect in a high dose of morphine via the NMDA-R/NO pathway.

中文翻译：

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吗啡耐受与戊四唑诱发小鼠癫痫阈值的相互作用：NMDA-受体/NO通路的作用

N-甲基-d-天冬氨酸受体（NMDA-R）/一氧化氮（NO）通路参与了阿片类药物镇痛作用的增强和阿片类药物耐受和依赖强度的降低。在目前的研究中，我们调查了 NMDA-R/NO 通路在慢性吗啡治疗小鼠中对吗啡镇痛作用耐受性的发展和戊四唑 (PTZ) 诱导的癫痫阈值的参与。吗啡 (30 mg/kg) 的长期治疗在吗啡诱导的耐受小鼠中表现出增加的癫痫发作抵抗力。当与 NOS 抑制剂和 NMDA-R 拮抗剂同时使用时，吗啡耐受的发展被取消，这表明对吗啡 (30 mg/kg) 的抗惊厥作用的耐受的发展是通过 NMDA-R/NO 途径介导的。在吗啡的急性治疗中证明了吗啡的剂量依赖性双相癫痫调节；0.5 mg/kg 剂量的急性治疗显示抗惊厥作用，30 mg/kg 剂量显示促惊厥作用。然而，在长期接受吗啡治疗的小鼠中观察到了不同的模式：它们在甩尾试验中表现出耐受性；连续五天用高剂量吗啡（30 毫克/公斤）长期治疗显示出抗惊厥作用，而低剂量吗啡（0.5 毫克/公斤）显示出促惊厥作用。吗啡的抗惊厥作用被同时给予 NO 合成酶 (NOS) 抑制剂完全抑制，包括非特异性 NOS 抑制剂（L-NAME，10 mg/kg）、诱导型 NOS 抑制剂（氨基胍，50 mg/kg）和神经元 NOS 抑制剂(7-硝基吲唑 (7-NI), 15 毫克/公斤）连续五天。此外，注射 NMDA-R 拮抗剂（MK-801，0.05 mg/kg）5 天显着抑制吗啡对 PTZ 诱导的阵挛性癫痫发作的抗惊厥作用。结果表明，长期服用吗啡会导致小鼠产生耐受性，进而可能通过 NMDA-R/NO 途径在高剂量吗啡中产生抗惊厥作用。