Abstract
The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and μ-opioid receptor upregulation in mice. On day 1 mice were implanted SC with a NTX or placebo pellet and injected IT and ICV with dH2O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse μ-opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected IT and ICV with dH2O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([3H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH2O treated mice by ≈ 70%. In binding studies, NTX significantly increased density of brain (≈ 60%) and spinal cord (≈ 140%) μ-opioid receptors without affecting affinity. The μ-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by ≈ twofold in placebo-treated mice. The oligodeoxynucleotide with four mismatches (Mismatch-4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse μ-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of μ-opioid receptors. Thus, μ-opioid antisense significantly reduced morphine potency without changing μ-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and μ-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of μ-opioid receptors does not involve changes in gene expression.
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