The effect of pretreatment with a δ₂-opioid receptor antisense oligodeoxynucleotide on the recovery from acute antinociceptive tolerance to δ₂-opioid receptor agonist in the mouse spinal cord

Abstract

1. An intrathecal (i.t.) injection of a selective δ₂-opioid receptor agonist, [D-Ala²]deltorphin II, produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [D-Ala²]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 δ₂-opioid receptor mRNA (δ-AS oligo) on the recovery from tolerance to [D-Ala²]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-Ala²]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-Ala²,NMePhe⁴,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 δ₂-opioid tolerance.

3. Treatment with [D-Ala²]deltorphin II (i.t.) significantly reduced the binding of [tyrosyl-3,5-³H(N)]-Tyr-D-Ser-Gly-Phe-Leu-Thr ([³H]-DSLET), a δ₂-opioid receptor agonist ligand, in the spinal cord 3 h after treatment, but binding returned to control levels by 24 h after treatment. However, [³H]-DSLET binding in the spinal cord remained significantly reduced at 24 h if δ-AS oligo (163 pmol) was coadministered with [D-Ala²]deltorphin II (6.4 nmol).

4. Based on these findings, it is concluded that a single stimulation of spinal cord δ₂-opioid receptors by intrathecally-administered [D-Ala²]deltorphin II induces a long-lasting desensitization of δ₂-opioid receptors to [D-Ala²]deltorphin II. Recovery from δ₂-opioid receptor-mediated antinociceptive tolerance apparently depends on replenishment by newly synthesized δ₂-opioid receptor protein rather than immediate reversal of δ₂-opioid receptors.

Full Text

The Full Text of this article is available as a PDF (348.4 KB).