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NEUROPHARMACOLOGY

An Antisense Oligonucleotide to the N-Methyl-D-aspartate (NMDA) Subunit NMDAR1 Attenuates NMDA-Induced Nociception, Hyperalgesia, and Morphine Tolerance

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (N.S., M.S., A.M.D., C.E.I.); and Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska (D.T.M.)

We determined whether the i.t. administration of an 18-mer phosphodiester antisense oligodeoxynucleotide (ODN) that reduces the expression of the rat NMDAR1 subunit of the N-methyl-D-aspartate (NMDA) receptor would affect nociceptive behaviors and prevent the development of morphine tolerance. Rats received 5 µl of i.t. saline, 30 nM antisense, or mismatch ODN twice a day for 5 days (NMDA-induced nociception, NMDA-induced thermal hyperalgesia, NR1 mRNA, and ligand binding studies) or for 3 days (formalin study). For the tolerance study, 5 days of ODNs or saline were followed by 3 days of concurrent administration of ODNs or saline (twice a day) and i.t. morphine (three times a day). Antisense, but not mismatch, results in the reduction of formalin phase 2 flinching by 50%, the spinal cord dorsal horn levels of NMDAR1 mRNA by 30%, and ligand binding by 50%. The i.t. ED₅₀ for NMDA-induced nociceptive behaviors is doubled, and thermal hyperalgesia is blocked by antisense treatment. The effects of antisense on NMDA-induced nociception and thermal hyperalgesia are completely reversed by discontinuing antisense. The coadministration of antisense with increasing doses of i.t. morphine for 3 days attenuates the development of morphine tolerance. These results demonstrate that an in vivo antisense targeting of the NMDAR1 subunit results in antihyperalgesic effects and a partial blockade of spinal morphine tolerance. They provide additional support for the critical role of the NMDA receptor in these forms of spinal nociception and in the development of morphine tolerance and suggest the potential therapeutic utility of this approach.

Address correspondence to: Dr. Charles E. Inturrisi, Department of Pharmacology, Weill Medical College of Cornell University, Room LC-524, 1300 York Ave., New York, NY 10021. E-mail: ceintur{at}med.cornell.edu

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