Received for publication July 29, 2008.
Revised October 27, 2008.
Accepted for publication October 27, 2008.

Deletion of the GluR5 subunit of kainate receptors affects the development of morphine tolerance

Abstract

Previous reports utilizing pharmacological antagonists implicate kainate receptor (KAR) activation in the development of morphine tolerance, dependence, conditioned place preference (CPP) and locomotor sensitization, but the role of GluR5-containing KAR in these effects remains unclear due to limited selectivity of the inhibitors employed. Therefore, we examined behavioral responses to systemic morphine in mice expressing a constitutive deletion of GluR5 (GluR5 KO). Unlike wildtype (WT) littermates, GluR5 KO mice do not develop tolerance following repeated morphine administration by subcutaneous (s.c.) injection or via s.c. pellet implantation. In contrast, GluR5 KO mice do not differ from WT with respect to thermal or mechanical nociceptive thresholds, acute morphine antinociception, morphine disposition in the central nervous system (CNS), morphine physical dependence as revealed by naloxone-precipitated withdrawal, or the development of place preference and locomotor hyper-responsiveness following chronic morphine administration. Surprisingly, the continuous s.c. infusion of the GluR2/GluR5-preferring antagonist LY293558 decreased the number of naloxone-precipitated jumps to a similar extent in WT and GluR5 KO mice. We observed opioid-induced hypersensitivity in both groups during morphine withdrawal as demonstrated by equivalent reductions in thermal and mechanical thresholds; however, this hypersensitivity was not evident during continuous systemic morphine infusion. Collectively, these data indicate that KAR containing the GluR5 subunit contribute to the development of morphine tolerance without affecting nociceptive thresholds, morphine analgesia or the disposition in CNS of morphine and its metabolite morphine-3-glucuronide. In addition, constitutive deletion of GluR5 does not alter the morphine-induced increase in locomotor activity or the acquisition of morphine reward as measured by a CPP paradigm.

Key words: conditioned place preference, glutamate, ionotropic receptor, knockout, locomotor sensitivity, opioid