THE EFFECT OF MU-OPIOID RECEPTOR ANTISENSE ON MORPHINE POTENCY AND ANTAGONIST-INDUCED SUPERSENSITIVITY AND RECEPTOR UP-REGULATION

The present study examined the effect of in vivo antisense oligodeoxyn ucleotide treatment on naltrexone (NTX)induced functional supersensiti vity and mu-opioid receptor upregulation in mice. On day 1 mice were i mplanted SC with a NTX or placebo pellet and injected IT and ICV with dH(2)O or oligodeoxynucleotides. The oligodeoxynucleotides were design ed so that they were either perfectly complementary to the first 18 ba ses of the coding region of mouse mu-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 dH(2)O or one of the oligodeo xynucleotides. After the final injections on day 9, placebo and NTX pe llets were removed, and 24 h later mice were tested for morphine analg esia or sacrificed for saturation binding studies ([H-3]DAMGO). Naltre xone increased the analgesic potency of morphine in dH(2)O treated mic e by approximate to 70%. In binding studies, NTX significantly increas ed density of brain (approximate to 60%) and spinal cord (approximate to 140%) mu-opioid receptors without affecting affinity. The mu-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by approximate to twofo ld in placebo-treated mice. The oligodeoxynucleotide with four mismatc hes (Mismatch-4) did not significantly alter morphine potency. When pl acebo-treated mice were treated with either the antisense to the mouse mu-opioid receptor, Mismatch-4 or Mismatch-1 there were no significan t changes in the density of mu-opioid receptors. Thus, mu-opioid antis ense significantly reduced morphine potency without changing mu-opioid receptor density. When NTX and oligodeoxynucleotide treatments were c ombined, there was no change in NTX-induced supersensitivity and mu-op ioid receptor upregulation. These data suggest that opioid antagonist- induced supersensitivity and upregulation of mu-opioid receptors does not involve changes in gene expression. (C) 1997 Elsevier Science Inc.