Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats

The NMDA receptor has been implicated in opioid tolerance and withdrawal. T he effects of continuous infusion of butorphanol on the modulation of NMDA receptor subunit NR1. NR2A, NR2B, and NR2C gene expression were investigate d by using in situ hybridization technique. Continuous intracerebroventricu lar (i.c.v.) infusion with butorphanol (26 nmol/mul/h) resulted in signific ant modulations in the NR1, NR2A, and NR2B mRNA levels. The level of NR1 mR NA was significantly decreased in the cerebral cortex, thalamus, and CA1 ar ea of hippocampus in butorphanol tolerant and withdrawal (7 h after stoppin g the infusion) rats. The NR2A mRNA was significantly decreased in the CA1 and CA3 of hippocampus in tolerant rats and increased in the cerebral corte x and dentate gyrus in butorphanol withdrawal rats. NR2B subunit mRNA was d ecreased in the cerebral cortex, caudate putamen, thalamus, CA3 of hippocam pus in butorphanol withdrawal rats. No changes of NR1, NR2A, NR2C subunit m RNA in the cerebellar granule cell layer were observed in either butorphano l tolerant or withdrawal rats. Using quantitative ligand autoradiography, t he binding of NMDA receptor ligand [H-3]MK-801 was increased significantly in all brain regions except in the thalamus and hippocampus, at the 7 hr af ter stopping the butorphanol infusion. These results suggest that region-sp ecific changes of NMDA receptor subunit mRNA (NR1 and NR2) as well as NMDA receptor binding ([H-3]MK-801) are involved in the development of tolerance to and withdrawal from butorphanol.