Morphine and MK-801 administration leads to alternative N-methyl-D-aspartate receptor 1 splicing and associated changes in reward seeking behavior and nociception on an operant orofacial assay.

The NMDA receptor plays a large role in opioid-induced plastic changes in the nervous system. The expression levels of its NR1 subunit are altered dramatically by morphine but no changes in its alternative splicing have been reported. Changes in the splicing of the N1, C1, C2, and C2' cassettes can alter the pharmacology and regulation of this receptor. Western Blots run on brain tissue from rats made tolerant to morphine revealed altered splicing of the N1 cassettes in the accumbens and amygdala (AMY), and the C1 cassette in the AMY and the dorsal hippocampus (HIPP). After 3days of withdrawal C2'-containing NR1 subunits were down-regulated in each of these areas. These were not due to acute doses of morphine and may represent long-term alterations in drug-induced neuroplasticity. We also examined the effects of morphine tolerance on an operant orofacial nociception assay which forces an animal to endure an aversive heat stimulus in order to receive a sweet milk reward. Morphine decreased pain sensitivity as expected but also increased motivational reward seeking in this task. NMDAR antagonism potentiated this reward seeking behavior suggesting that instead of attenuating tolerance, MK-801 may actually alter the rewarding and/or motivational properties of morphine. When combined, MK-801 and morphine had an additive effect which led to altered splicing in the accumbens, AMY, and the HIPP. In conclusion, NR1 splicing may play a major role in the cognitive behavioral aspects especially in motivational reward-seeking behaviors.