The Roles of Excitatory Amino Acids and Cytokines in Morphine Tolerance: Effect of Tricyclic Antidepressant Amitriptylin

Yueh-Hua Tai1, Wen-Jinn Liaw 1, Yuan-Xiang Tao2, Chih-Shung Wong*, 1
1 Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan,R.O.C
2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., 367 Ross, Baltimore, Maryland 21205, USA

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© 2009 Tai et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, R.O.C; Tel: +886-2-87927008; Fax: +886-2-87927009; E-mail:


Morphine is an effective analgesic in clinical practice; however, its long-term administration causes tolerance, thereby limiting its use. The development of opioid tolerance and its associated hyperalgesia has been associated with interactions between opioid receptors and excitatory amino acids or cytokines. Targeted inhibition of excitatory amino acid- and cytokine-mediated signaling pathways may allow development of novel therapeutic strategies for treating opioid tolerance. Recent studies showed that administration of amitriptyline (a tricyclic antidepressant widely used in the treatment of neuropathic pain) attenuated morphine tolerance and preserved the antinociceptive effect of morphine. This ability might be related to the effects of tricyclic antidepressants on pro-inflammatory cytokine release and glutamate transporter expression in dorsal horn during morphine tolerance. Here, we will review evidence for the role of excitatory amino acids and cytokines in the development of morphine tolerance and discuss potential mechanisms by which tricyclic antidepressants attenuate morphine tolerance.