Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: Role of the PSD-95/NR1/nNOS/PKC纬 signaling pathway

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• 作者：Ya-Ni Huang^a ; ^b ; Ru-Yin Tsai^b ; Shinn-Long Lin^c ; Chih-Cheng Chien^d ; Chen-Hwan Cherng^c ; Ching-Tang Wu^c ; Chun-Chang Yeh^c ; Chih-Shung Wong^b ; ^c ; ^e ; ^{w82556@gmail.com}
• 关键词：Amitriptyline ; Astrocyte activation ; Morphine tolerance ; PSD-95 ; NMDA receptors ; NR1 subunit ; nNOS ; PKC纬
• 刊名：Behavioural Brain Research
• 出版年：2012
• 期刊代码：3_01664328
• 类别：neu
• 出版时间：15 April, 2012
• 卷：229
• 期：2
• 页码：401-411
• 文件大小：1547 K

摘要

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 (PKC纬), 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/PKC纬 signaling in morphine tolerance. Male Wistar rats were implanted with an intrathecal catheter and received an intrathecal infusion of saline or amitriptyline (15 渭g/h), morphine + saline (tolerance induction, 15 渭g/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 PKC纬 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/PKC纬 signaling cascade.