An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance

The Journal of Pharmacology and Experimental Therapeutics
Naohito ShimoyamaCharles E Inturrisi

Abstract

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 microl 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. ED(50) 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 mor...Continue Reading

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Citations

May 8, 2010·The Journal of Biological Chemistry·Carol K L LamTony K T Lam
Sep 16, 2006·Peptides·Richard J Bodnar, Gad E Klein
Feb 3, 2009·The Journal of Pain : Official Journal of the American Pain Society·Sandra M GarrawayCharles E Inturrisi
Dec 17, 2009·Pain·Amanda R WeyerbacherCharles E Inturrisi
Apr 11, 2008·European Journal of Anaesthesiology·B P Sweeney, M Z Michel
Oct 31, 2009·Molecular Neurobiology·Max Larsson
Jun 7, 2007·The Journal of Pharmacology and Experimental Therapeutics·Sandra M GarrawayCharles E Inturrisi
Apr 21, 2017·Oncotarget·Jian WangWangyuan Zou
Feb 15, 2020·Journal of Addiction Medicine·Andrew J Saxon
Mar 31, 2021·Experimental Neurology·Tao WangShuanglin Hao
Feb 1, 2011·Free Radical Biology & Medicine·Daniela SalveminiWilliam L Neumann

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