Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan.
Behav Brain Res. 2012 Apr 15;229(2):401-11. doi: 10.1016/j.bbr.2012.01.044. Epub 2012 Jan 30.
The tricyclic antidepressant amitriptyline binds with high affinity to N-methyl-d-aspartate receptors (NMDARs) and inhibits NMDAR-mediated events. Activation of the postsynaptic density protein-95 (PSD-95)/NMDAR-mediated downstream signaling cascade, including neuronal nitric oxide synthase (nNOS) and protein kinase gamma (PKCγ), has been shown to be involved in morphine tolerance. The present study examined the potential effect of amitriptyline on chronic morphine infusion-induced spinal PSD-95/NMDAR/nNOS/PKCγ signaling in morphine tolerance. Male Wistar rats were implanted with an intrathecal catheter and received an intrathecal infusion of saline or amitriptyline (15 μg/h), morphine+saline (tolerance induction, 15 μg/h), or morphine+amitriptyline for 5 days. Co-administration of amitriptyline with morphine not only preserved the antinociceptive effect of morphine, but also attenuated astrocyte activation in the rat spinal cord dorsal horn. On day 5 after drug infusion, increased expression and phosphorylation of spinal membrane NMDAR NR1 subunit and expression of PSD-95 were observed following chronic morphine infusion and these effects were attenuated by amitriptyline co-infusion. Upregulation of NMDAR-induced intracellular nNOS expression was also inhibited by amitriptyline co-infusion in chronic morphine-infused rats. Furthermore, amitriptyline co-infusion significantly inhibited morphine-induced PKCγ expression in both the cytosol and membrane of spinal neurons. These findings suggest that the attenuation of morphine tolerance caused by amitriptyline is due to downregulation of NMDAR NR1 subunit expression in the synaptosomal membrane accompanied by decreased expression of the scaffolding protein PSD-95. The effects of amitriptyline in attenuating astrocyte activation and reversing tolerance to morphine may be due, at least in part, to inhibition of the PSD-95/NMDAR NR1/nNOS/PKCγ signaling cascade.
三环类抗抑郁药阿米替林与 N-甲基-D-天冬氨酸受体 (NMDAR) 高亲和力结合，并抑制 NMDAR 介导的事件。已表明，突触后密度蛋白-95 (PSD-95)/NMDAR 介导的下游信号级联，包括神经元型一氧化氮合酶 (nNOS) 和蛋白激酶γ (PKCγ) 的激活，与吗啡耐受有关。本研究探讨了阿米替林对慢性吗啡输注诱导的吗啡耐受脊髓 PSD-95/NMDAR/nNOS/PKCγ 信号的潜在影响。雄性 Wistar 大鼠植入鞘内导管，并接受鞘内输注盐水或阿米替林（15 μg/h）、吗啡+盐水（耐受诱导，15 μg/h）或吗啡+阿米替林 5 天。阿米替林与吗啡联合给药不仅保留了吗啡的镇痛作用，而且减轻了大鼠脊髓背角星形胶质细胞的激活。在药物输注后第 5 天，慢性吗啡输注后观察到脊髓膜 NMDAR NR1 亚基表达和磷酸化增加以及 PSD-95 表达增加，这些效应被阿米替林共输注减弱。NMDAR 诱导的细胞内 nNOS 表达的上调也被慢性吗啡输注大鼠中的阿米替林共输注抑制。此外，阿米替林共输注显著抑制吗啡诱导的脊髓神经元细胞质和膜中 PKCγ 的表达。这些发现表明，阿米替林引起的吗啡耐受减弱是由于突触体膜中 NMDAR NR1 亚基表达下调，同时支架蛋白 PSD-95 表达降低所致。阿米替林减轻星形胶质细胞激活和逆转吗啡耐受的作用可能至少部分归因于抑制 PSD-95/NMDAR NR1/nNOS/PKCγ 信号级联。
