Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats

W. J. Liaw, B. Zhang, F. Tao, M. Yaster, R. A. Johns, Y. X. Tao

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The activation of spinal cord N-methyl-D-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 μg/10 μl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 μg/10 μl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 μg/10 μl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function. The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance.

Original languageEnglish (US)
Pages (from-to)11-15
Number of pages5
JournalNeuroscience
Volume123
Issue number1
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Antisense technology
  • Hyperalgesia
  • Intrathecal injection
  • NMDA receptors
  • Opioid tolerance

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