title: 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.
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Chiao
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000502:physiology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000502:physiology*; D004361:Drug Tolerance; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D011493:Protein Kinase C / Q000502:physiology*; D017470:Receptors, Glutamate / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D027322:Amino Acid Transport System X-AG; D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D018698:Glutamic Acid; D011493:Protein Kinase C