Intracerebroventricular (i.c.v.) pretreatment of male ICR mice with beta-endorphin (0.6 nmol) or intrathecal (i.t.) pretreatment with antisense oligodeoxynucleotide to delta-opioid receptor mRNA (163 pmol) alone given 24 h earlier did not have any effect on i.t. administered delta-opioid receptor agonist [D-Ala2]deltorphin II (6.4 nmol)-induced antinociception. However, a concomitant i.c.v. pretreatments with beta-endorphin (0.08-0.6 nmol) and i.t. pretreatment with delta-opioid receptor antisense oligodeoxynucleotide (163 pmol) for 24 h dose-dependently attenuated i.t. challenged [D-Ala2]deltorphin II-induced antinociception. A concomitant i.c.v. pretreatment with mu-opioid receptor agonist [D-Ala2,N MePhe4,Gly(ol)5]enkephalin (DAMGO) or kappa-opioid receptor agonist U50,488H and i.t. pretreatment with delta-opioid receptor antisense oligodeoxynucleotide for 24 h did not affect i.t. challenged [D-Ala2]deltorphin II-induced antinociception. beta-Endorphin given supraspinally has been documented to release [Met5]enkephalin acting on delta-opioid receptors in the spinal cord. Our results indicate that supraspinal pretreatment with beta-endorphin selectively causes a loss of spinal delta-opioid receptor-mediated antinociception in mice receiving delta-opioid receptor antisense oligodeoxynucleotide.