Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: Evidence for opposing NO actions on morphine analgesia and tolerance

Yuri A. Kolesnikov, Ying Xian Pan, Anna Marie Babey, Subash Jain, Roger Wilson, Gavril W. Pasternak

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Down- regulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with N(G)-nitro-L- arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down- regulate splice variants opens many areas in the study of nNOS and other proteins.

Original languageEnglish (US)
Pages (from-to)8220-8225
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number15
DOIs
StatePublished - Jul 22 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • MOR-1
  • Nu receptor
  • Opioid

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