1-Aminocyclopropane carboxylic acid (ACPC), a partial agonist of the glycine site on the NMDA receptor, prevents tolerance to the mu opioid morphine and the delta ligand [D-Pen2,D-Pen5]enkephalin (DPDPE) when co-administered with the opioid. In contrast, ACPC does not significantly influence tolerance to the kappa1 opioid U50,488H or the kappa3 ligand naloxone benzoylhydrazone (NalBzoH). The actions of ACPC are restricted to tolerance. When given alone, ACPC has no analgesic actions in the tailflick assay and it does not change morphine's ED50 in naive mice. Chronic administration of ACPC alone for 5 days does not affect the sensitivity of mice to morphine. ACPC also reverses preexisting tolerance. When mice are made tolerant to morphine over 5 days and then receive ACPC along with their morphine, analgesia returns to naive levels within 3 days despite the continued administration of morphine. The actions of ACPC on opioid tolerance correspond closely with those previously described with both competitive and non-competitive NMDA antagonists.