The effect of pretreatment with a δ 2 ‐opioid receptor antisense oligodeoxynucleotide on the recovery from acute antinociceptive tolerance to δ 2 ‐opioid receptor agonist in the mouse spinal cord

1 An intrathecal (i.t.) injection of a selective δ 2 ‐opioid receptor agonist, [D‐Ala 2 ]deltorphin II, produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [d‐Ala 2 ]deltorphin II. This acute tolerance lasted 3 to 9 h and completely subsided by 12 h. The experiments were designed to examine the effect of pretreatment with an antisense oligodeoxynucleotide to δ 2 ‐opioid receptor mRNA (δ‐AS oligo) on the recovery from tolerance to [D‐Ala 2 ]deltorphin II‐induced antinociception in male ICR mice. 2 Pretreatment with δ‐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 2 ]deltorphin II‐induced antinociception in a dose‐dependent manner. However, treatment with δ‐AS oligo (163 pmol) did not prevent the recovery from tolerance to either the μ‐opioid receptor agonist [D‐Ala 2 ,NMePhe 4 ,Gly(ol) 5 ]enkephalin (DAMGO) or the κ‐opioid receptor agonist U50,488H, indicating subtype specificity in the mechanism by which δ‐AS oligo inhibits recovery from δ 2 ‐opioid tolerance. 3 Treatment with [D‐Ala 2 ]deltorphin II (i.t.) significantly reduced the binding of [tyrosyl‐3,5‐ 3 H(N)]‐Tyr‐D‐Ser‐Gly‐Phe‐Leu‐Thr ([ 3 H]‐DSLET), a δ 2 ‐opioid receptor agonist ligand, in the spinal cord 3 h after treatment, but binding returned to control levels by 24 h after treatment. However, [ 3 H]‐DSLET binding in the spinal cord remained significantly reduced at 24 h if δ‐AS oligo (163 pmol) was coadministered with [D‐Ala 2 ]deltorphin II (6.4 nmol). 4 Based on these findings, it is concluded that a single stimulation of spinal cord δ 2 ‐opioid receptors by intrathecally‐administered [D‐Ala 2 ]deltorphin II induces a long‐lasting desensitization of δ 2 ‐opioid receptors to [D‐Ala 2 ]deltorphin II. Recovery from δ 2 ‐opioid receptor‐mediated antinociceptive tolerance apparently depends on replenishment by newly synthesized δ 2 ‐opioid receptor protein rather than immediate reversal of δ 2 ‐opioid receptors.