NMDA-R1 antisense oligonucleotide attenuates withdrawal signs from morphine

To test the involvement of NMDA receptor in the development of physical dependence on opioid, the effects of an antisense oligonucleotide against NMDA receptors on the naloxone precipitated withdrawal from morphine were studied. Antisense oligonucleotide (15 nmol/5 microl) corresponding to the nucleotides 4-21 of rat NMDA-RI subunit, sense oligonucleotide, or saline was injected into the lateral ventricle of rats every 12 h for 6 days. On day 4, the rats were intracerebroventricularly (i.c.v.) infused with morphine (26 nmol microl(-1) h(-1)) through osmotic minipumps. Rats then received simultaneous treatment with morphine and oligonucleotides or saline for 3 days. Antisense oligonucleotide, but not saline or sense oligonucleotide, significantly attenuated naloxone precipitated withdrawal signs including jumping, rearing, stretching, teeth chattering, vocalization, and penis licking. Treatment with antisense oligonucleotide, but not sense oligonucleotide, significantly reduced the Bmax of [3H]MK801 ¿[3-3H](+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10- imine¿ binding without significant changes in Kd. These results support the hypothesis that NMDA receptors are involved in the physical dependence on opioid.