Opioid tolerance: is there a dialogue between glutamate and beta-arrestin?

Abstract

Opioids are widely used as analgesics in clinical pain management for decades. However, opioid tolerance is a serious problem which limits their usefulness. The mechanisms of opioid tolerance are complex which involve many regulatory factors. Glutamate is an important extracellular neurotransmitter which activates glutamate receptor and induces a series of signal transduction to regulate the development of opioid tolerance. Previous studies have indicated an involvement of NMDA receptors in the development of beta-opioid tolerance and associated abnormal pain sensitivity. Many NMDA receptor antagonists had been demonstrated to regulate morphine tolerance development. In the NMDA-mediated intracellular mechanisms of opioid tolerance, protein kinase C (PKC) modulates beta-opioid receptor activation. Besides, the opioid receptor desensitization involves phosphorylation of receptors and subsequent binds to beta-arrestin. In knockout mice, lacking beta-arrestin-2, desensitization of beta-opioid receptor did not occur after chronic morphine treatment, and these animals also failed to develop antinociceptive tolerance. Moreover, morphine tolerance can be completely reversed with a low dose of the classical PKC inhibitor chelerythrine in the beta-arrestin-2 knock-out, but not wild-type mice. These findings indicate that, in the absence of beta-arrestin-2, contributions of PKC-dependent regulatory system would become apparent. In summary, PKC is regulated by NMDA receptors to affect the development of opioid tolerance, beta-arrestin-2 also influences PKC-induced opioid receptor desensitization. PKC may play an important role to coordinate these factors which regulate opioid tolerance.