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: Yu-Chung Chiao, Chih-Shung Wong
• Journal: Acta anaesthesiologica Taiwanica : official journal of the Taiwan Society of Anesthesiologists (Acta Anaesthesiol Taiwan) Vol. 42 Issue 2 Pg. 93-101 (Jun 2004) ISSN: 1875-4597 [Print] China (Republic : 1949- )
• PMID: 15346705 (Publication Type: Journal Article, Review)

Chemical References

• ARRB2 protein, human
• Amino Acid Transport System X-AG
• Analgesics, Opioid
• Arrb2 protein, mouse
• Arrestins
• Receptors, Glutamate
• Receptors, N-Methyl-D-Aspartate
• beta-Arrestin 2
• beta-Arrestins
• Glutamic Acid
• Protein Kinase C

Topics

• Amino Acid Transport System X-AG (physiology)
• Analgesics, Opioid (pharmacology)
• Animals
• Arrestins (physiology)
• Drug Tolerance
• Glutamic Acid (physiology)
• Humans
• Protein Kinase C (physiology)
• Receptors, Glutamate (physiology)
• Receptors, N-Methyl-D-Aspartate (physiology)
• beta-Arrestin 2
• beta-Arrestins