Tai Yueh-Hua, Wang Yu-Hsueh, Wang Jhi-Joung, Tao Pao-Luh, Tung Che-Se, Wong Chih-Shung
Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
Pain. 2006 Sep;124(1-2):77-86. doi: 10.1016/j.pain.2006.03.018. Epub 2006 May 11.
The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on morphine tolerance in rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters with or without a microdialysis probe, then received a continuous i.t. infusion of saline (control) or morphine (15 microg/h) and/or amitriptyline (15 microg/h) for 5 days. The results showed that amitriptyline alone did not produce an antinociceptive effect, while morphine alone induced antinociceptive tolerance and down-regulation of spinal glutamate transporters (GLAST, GLT-1, and EAAC1) in the rat spinal cord dorsal horn. Co-administration of amitriptyline with morphine attenuated morphine tolerance and up-regulated GLAST and GLT-1 expression. On day 5, morphine challenge (10 microg/10 microl) resulted in a significant increase in levels of the excitatory amino acids (EAAs), aspartate and glutamate, in CSF dialysates in morphine-tolerant rats. Amitriptyline co-infusion not only markedly suppressed this morphine-evoked EAA release, but also preserved the antinociceptive effect of acute morphine challenge at the end of infusion. Glial cells activation and increased cytokine expression (TNFalpha, IL-1beta, and IL-6) in the rat spinal cord were induced by the 5-day morphine infusion and these neuroimmune responses were also prevented by amitriptyline co-infusion. These results show that amitriptyline not only attenuates morphine tolerance, but also preserves its antinociceptive effect. The mechanisms involved may include: (a) inhibition of pro-inflammatory cytokine expression, (b) prevention of glutamate transporter down-regulation, and even up-regulation of glial GTs GLAST and GLT-1 expression, with (c) attenuation of morphine-evoked EAA release following continuous long-term morphine infusion.
本研究旨在评估三环类抗抑郁药阿米替林对大鼠吗啡耐受性的影响。雄性Wistar大鼠植入两根鞘内（i.t.）导管，其中一根带有或不带有微透析探针，然后连续5天接受鞘内输注生理盐水（对照）或吗啡（15微克/小时）和/或阿米替林（15微克/小时）。结果表明，单独使用阿米替林不会产生抗伤害感受作用，而单独使用吗啡会诱导大鼠脊髓背角产生抗伤害感受耐受性并下调脊髓谷氨酸转运体（GLAST、GLT-1和EAAC1）。阿米替林与吗啡联合给药可减轻吗啡耐受性并上调GLAST和GLT-1表达。在第5天，吗啡激发（10微克/10微升）导致吗啡耐受大鼠脑脊液透析液中兴奋性氨基酸（EAA）天冬氨酸和谷氨酸水平显著升高。联合输注阿米替林不仅显著抑制了这种吗啡诱发的EAA释放，还在输注结束时保留了急性吗啡激发的抗伤害感受作用。5天的吗啡输注诱导了大鼠脊髓中的胶质细胞活化和细胞因子表达增加（TNFα、IL-1β和IL-6），联合输注阿米替林也可预防这些神经免疫反应。这些结果表明，阿米替林不仅可减轻吗啡耐受性，还可保留其抗伤害感受作用。涉及的机制可能包括：（a）抑制促炎细胞因子表达，（b）防止谷氨酸转运体下调，甚至上调胶质细胞GTs GLAST和GLT-1表达，以及（c）在持续长期吗啡输注后减轻吗啡诱发的EAA释放。
