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

   

Authors:	Kolesnikov, Y. A.; Pan, Y. X.; Babey, A. M.; Jain, S.; Wilson, R.; Pasternak, G. W.
Article Title:	Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: Evidence for opposing NO actions on morphine analgesia and tolerance
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.
Keywords:	controlled study; nonhuman; mouse; animals; mice; animal experiment; neuromodulation; neurons; enzyme activity; central nervous system; animalia; messenger rna; alternative rna splicing; morphine; opioid; analgesia; morphine sulfate; drug tolerance; mu opiate receptor; nitric oxide synthase; isoenzymes; nitroarginine; oligonucleotides, antisense; nitric oxide; receptor down regulation; mor-1; antisense oligodeoxynucleotide; subcutaneous drug administration; intracerebroventricular drug administration; male; priority journal; article; n(g) nitroarginine; nu receptor; nitric oxide synthase inhibitor; neuropharmacology
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	94
Issue:	15
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	1997-07-22
Start Page:	8220
End Page:	8225
Language:	English
DOI:	10.1073/pnas.94.15.8220
PUBMED:	9223342
PROVIDER:	scopus
PMCID:	PMC21584
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0030743849&doi=10.1073%2fpnas.94.15.8220&partnerID=40&md5=97b575f472428c504ccd68903eebfba4
Notes:	Article -- Export Date: 17 March 2017 -- Source: Scopus

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