Opioid tolerance and dependence: A new model highlighting the role of metabotropic glutamate receptors

Abstract

Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca 2+ ). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.