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

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 acidand 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.