Tolerance, Withdrawal and Glutamate Release: From the Preclinical Study

摘要

Using a rat model of continuous morphine infusion, the following results were obtained. 1) Tolerance development was aggravated by the periodic reversal of morphine action. 2) Intermittent opiate receptor occupancy led to progressively greater glutamate release and a more pronounced tolerance. 3) Acute reversal of morphine by naloxone evoked an immediate increase in spinal glutamate release. 4) The degree of precipitated withdrawal significantly correlated with the increase in glutamate release. 5) Pretreatment immediately before naloxone-induced withdrawal with clonidine (alpha-2 agonist), MK-801 (noncompetitive NMDA antagonist), or AP-5 (competitive NMDA antagonist) suppressed the increase in glutamate release and behavioral signs of withdrawal. 6) Inhalation anesthesia also inhibited naloxone-induced glutamate release and withdrawal signs.