THE neuronal intracellular calcium-binding protein cal-bindin D28k is a neurochemical marker in the striatum, normally expressed in the matrix compartment and absent from the mu-opiate receptor-enriched striosomal (patch) compartment. Because chronic treatment with morphine has been reported to increase calcium levels in synaptosomes of rat striatum, we studied effects of morphine on calbindin immunoreactivity (ir) in rat brain, using immunocytochemistry. Treatment with morphine for 5 days increased calbindin-ir in the striatal matrix, and induced intense calbindin-ir in the patch compartment. Increased calbindin-ir in patches persisted through day 14 post-morphine. Co-administration of the NMDA receptor antagonist MK-801 blocked the morphine-induced increase in calbindin-ir in patches. We suggest that chronic morphine treatment may increase calcium and calbindin levels via increased glutamatergic transmission in striatum. These findings are consistent with reports that MK-801 inhibits tolerance to morphine, and provide a possible mechanism and anatomical substrate for this inhibition.