Antisense oligodeoxynucleotides to mu- and delta-opioid receptor mRNA block the enhanced effects of opioids during intestinal inflammation.

Intestinal inflammation enhances the inhibitory effects of mu- and delta-opioids in the gut, possibly related to an increased receptor expression. We evaluated the effects of opioids after intraperitoneal administration of antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA. Inflammation was induced in mice by intragastric administration of croton oil; gastrointestinal transit was assessed with charcoal and permeability with [51Cr]etylenediaminetetraacetate ([51Cr]EDTA). Baseline values were unaltered after antisense oligodeoxynucleotides. In controls, antisense oligodeoxynucleotides to mu-opioid receptor mRNA decreased the antitransit effects of morphine (27%) and [N-MePhe3D-Pro4]morphiceptin (PL017) (26%), and the reduction was significantly greater during inflammation (50% and 47%). A similar effect was observed on permeability (control: 41-21% decrease; inflamed: 66-45%). In both assays, antisense oligodeoxynucleotides to delta-opioid receptor mRNA also reduced the effects of [D-Pen2,5]enkephalin (DPDPE) in a higher percentage during inflammation (43-32% controls, 60-49% inflamed). We show that antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA are efficiently blocking the intestinal effects of opioids during inflammation, suggesting that an increased transcription of these receptors in the gut mediates the enhanced effects of opioids during inflammation.