The eect of pretreatment with a d2-opioid receptor antisense oligodeoxynucleotide on the recovery from acute antinociceptive tolerance to d2-opioid receptor agonist in the mouse spinal cord

1 An intrathecal (i.t.) injection of a selective d2-opioid receptor agonist, [D-Ala]deltorphin II, produced an acute antinociceptive tolerance to the antinociceptive e€ect of a subsequent i.t. challenge of [DAla]deltorphin II. This acute tolerance lasted 3 to 9 h and completely subsided by 12 h. The experiments were designed to examine the e€ect of pretreatment with an antisense oligodeoxynucleotide to d2-opioid receptor mRNA (d-AS oligo) on the recovery from tolerance to [D-Ala]deltorphin II-induced antinociception in male ICR mice. 2 Pretreatment with d-AS oligo (1.63 to 163 pmol, i.t.), but not mismatched oligo (MM oligo) (163 pmol), prevented the recovery from acute tolerance to [D-Ala]deltorphin II-induced antinociception in a dose-dependent manner. However, treatment with d-AS oligo (163 pmol) did not prevent the recovery from tolerance to either the m-opioid receptor agonist [D-Ala,NMePhe,Gly(ol)]enkephalin (DAMGO) or the k-opioid receptor agonist U50,488H, indicating subtype speci®city in the mechanism by which d-AS oligo inhibits recovery from d2-opioid tolerance. 3 Treatment with [D-Ala]deltorphin II (i.t.) signi®cantly reduced the binding of [tyrosyl-3,5-H(N)]Tyr-D-Ser-Gly-Phe-Leu-Thr ([H]-DSLET), a d2-opioid receptor agonist ligand, in the spinal cord 3 h after treatment, but binding returned to control levels by 24 h after treatment. However, [H]-DSLET binding in the spinal cord remained signi®cantly reduced at 24 h if d-AS oligo (163 pmol) was coadministered with [D-Ala]deltorphin II (6.4 nmol).