In vivo antisense inhibition of prodynorphin expression in rat striatum: dose-dependence and sequence specificity

Abstract

An antisense oligodeoxynucleotide (ODN) corresponding to a region downstream from the translation initiation codon of rat prodynorphin mRNA was constructed and obtained in its phosphothioated form. Sense and randomized ODNs were also used. Each ODN was continuously infused for 3 days into dorsal striatum of Sprague-Dawley rats, at three different concentrations, followed by measurement of radioimmunoactive dynorphin A and met-enkephalin, as well as total protein content in striatal tissue. Dynorphin A levels were reduced in a dose-dependent manner following both antisense and sense probes, but not by a control random sequence. Thus, antisense as well as sense ODNs specifically inhibited prodynorphin gene expression in striatum. These results indicate that direct continuous infusion of antisense ODNs into a defined brain region can be used to inhibit late-response gene expression.