The mesocorticolimbic circuitry has been implicated in the pathophysiology of several neuropsychiatric syndromes like chronic pain and addiction. The aim of this study was to evaluate the effects of dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on sensorimotor behaviors and the consequent changes in the dopamine, glutamate, and opiate systems in rats. Five groups of rats were subjected to acute tests for nociception (hot plate and paw pressure) before and after MK-801 (0.05, 0.1, 0.2 and 0.4 mg/kg, i.p.) or saline. Another two groups received daily i.p. saline or MK-801 (0.4 mg/kg) for 15 days. The nociceptive tests were performed on days 1, 7, and 14. On day 15 the rats received the last injection and were immediately sacrificed. We measured the mRNA expression, by in situ hybridization (ISH), of various dopamine and glutamate receptors, and enkephalin (Enk), dynorphin (Dyn), and substance P (SP) in the striatum, nucleus accumbens (NAC), piriform and cingulate cortex. Acute MK-801, dose-dependently, resulted in hyperalgesia. The chronic effects of 0.4 mg/kg MK-801 showed an extinction of the acute hyperalgesic effects especially with the hot plate test. The ISH studies revealed a decrease in mRNA expression of Enk and SP in the striatum and NAC. Our results indicate that the reversal of acute MK-801-induced hyperalgesia, with repeated exposure to systemic MK-801, is not directly related to changes in dopamine and glutamate receptors and might involve alteration of the striatal neuropeptide system.