Mechanisms of opioid tolerance

Abstract

This Commentary evaluates several observations and hypotheses made by Fundytus and Coderre: (1) Initial treatment with high doses of μ-opioid agonists decrease phosphatidlylinositol (PI) hydrolysis, while (2) chronic treatment increases PI hydrolysis to near control levels via increased activity of type I metabotropic glutamate receptors (mGluRs) and/or δ-opioid receptors. (3) The resulting inositol 1,4,5-trisphosphate-mediated increase in protein kinase C then phosphorylates a μ-opioid coupled G-protein, leading to a desensitization of μ-opioid receptors; phosphorylates N-methyl-D-aspartate (NMDA) receptor-associated Ca²⁺ channels, resulting in a release of these channels from an Mg²⁺ block; and increases Ca²⁺/calmodulin-dependent protein kinase, which produces additional phosphorylation of μ-opioid coupled G-protein, leading to further desensitization of μ-opioid receptors. (4) A role for type II/III mGluRs in opioid dependence occurs from desensitization of these receptors, which allows 3′,5′-cyclic adenosine monophosphate to remain at levels high enough to produce withdrawal symptoms. (5) Second messenger systems interact. We then review some of the observations with which a model of opioid tolerance should be consistent. Finally, we review a model for opioid tolerance that we recently proposed.