BLOCKADE OF U50,488H ANALGESIA BY ANTISENSE OLIGODEOXYNUCLEOTIDES TO A KAPPA-OPIOID RECEPTOR

The recently cloned kappa-opioid receptor has binding characteristics consistent with those of a kappa(1)-opioid receptor. Repeated intrathecal administration of an antisense oligodeoxynucleotide against the kappa(1)-opioid receptor selectively lowers U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetemide) analgesia (P<0.02) without affecting mu or delta analgesia. A mismatched antisense oligodeoxynucleotide in which 4 bases had been switched is inactive against U50,488H analgesia. These studies confirm at the molecular level traditional pharmacological studies implying a distinct receptor mechanisms for kappa(1) analgesia and demonstrate the utility of antisense approaches in studies of opioid pharmacology.