Tai Y-H, Tsai R-Y, Wang Y-H, Cherng C-H, Tao P-L, Liu T-M, Wong C-S
Department of Anesthesiology, Tri-service General Hospital and National Defense Medical Center, Taipei, Taiwan.
Neuroscience. 2008 May 15;153(3):823-31. doi: 10.1016/j.neuroscience.2008.02.055. Epub 2008 Mar 6.
We previously showed that intrathecal co-administration of amitriptyline with morphine upregulates the expression of the glial glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and restores neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression in chronically morphine-infused rats. The present study examined the role of nuclear transcription factor-kappaB (NF-kappaB) in the regulation of the expression of GLAST, GLT-1, and EAAC1 following long-term amitriptyline/morphine co-infusion. Male Wistar rats were implanted with two intrathecal catheters with or without a microdialysis probe; one of the catheters was used for continuous infusion of saline (control), morphine (15 microg/h), or morphine plus amitriptyline (both 15 microg/h) for 5 days, while the other was used for a single daily intrathecal injection of the NF-kappaB inhibitor Ro106-9920 (10 microl of 10 microM) for 5 days. We found that amitriptyline co-infusion restored the antinociceptive effect of morphine (4.5-fold right-shift in the morphine dose-response curve compared with a 65-fold right-shift in its absence) and this effect was inhibited by Ro106-9920 administration (48-fold right-shift). Moreover, amitriptyline/morphine co-infusion increased IkappaBalpha phosphorylation and the translocation of NF-kappaB p65 from the cytosol to the nucleus. Daily intrathecal injection of Ro106-9920 prevented the amitriptyline/morphine-induced NF-kappaB p65 translocation and reversed the amitriptyline/morphine-induced GLAST and GLT-1 upregulation and inhibited the restoration of EAAC1 expression. The Ro106-9920 injections abolished the inhibitory effect of amitriptyline on the morphine-evoked release of excitatory amino acids into the spinal cerebrospinal fluid (CSF) dialysates. In conclusion, amitriptyline/morphine co-infusion restores the antinociceptive effect of morphine and upregulates GLAST and GLT-1 expression and restores EAAC1 expression to baseline levels, thus reducing excitatory amino acid levels in the spinal CSF dialysates. The mechanism involves activation of the NF-kappaB pathway, but may also involve other pathways.
我们之前的研究表明，在长期注射吗啡的大鼠中，鞘内联合给予阿米替林和吗啡可上调胶质细胞谷氨酸转运体谷氨酸 - 天冬氨酸转运体（GLAST）和谷氨酸转运体 -1（GLT -1）的表达，并使神经元谷氨酸转运体兴奋性氨基酸载体1（EAAC1）的表达恢复至正常水平。本研究旨在探讨核转录因子 -κB（NF -κB）在长期联合输注阿米替林/吗啡后对GLAST、GLT -1和EAAC1表达调控中的作用。将雄性Wistar大鼠植入带有或不带有微透析探针的两根鞘内导管；其中一根导管用于连续5天输注生理盐水（对照组）、吗啡（15微克/小时）或吗啡加阿米替林（均为15微克/小时），另一根导管用于每天一次鞘内注射NF -κB抑制剂Ro106 - 9920（10微升10微摩尔/升），持续5天。我们发现，联合输注阿米替林可恢复吗啡的镇痛作用（吗啡剂量 - 反应曲线右移4.5倍，而单独输注吗啡时右移65倍），且Ro106 - 9920的给药可抑制这种作用（右移48倍）。此外，联合输注阿米替林/吗啡可增加IκBα的磷酸化以及NF -κB p65从细胞质向细胞核的转位。每天鞘内注射Ro106 - 9920可阻止阿米替林/吗啡诱导的NF -κB p65转位，并逆转阿米替林/吗啡诱导的GLAST和GLT -1上调，同时抑制EAAC1表达的恢复。注射Ro10-69920消除了阿米替林对吗啡诱发的兴奋性氨基酸释放到脊髓脑脊液（CSF）透析液中的抑制作用。总之，联合输注阿米替林/吗啡可恢复吗啡的镇痛作用，上调GLAST和GLT -1的表达，并使EAAC1表达恢复至基线水平，从而降低脊髓CSF透析液中兴奋性氨基酸的水平。其机制涉及NF -κB途径的激活，但也可能涉及其他途径。
