The effect of mu-opioid receptor antisense on morphine potency and antagonist-induced supersensitivity and receptor upregulation.
The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and mu-opioid receptor up-regulation in mice. On day 1 mice were implanted S.C. with a NTX or placebo pellet and injected I.T. and I.C.V. 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 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 I.T. and I.C.V. 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 approximately 70%. In binding studies, NTX significantly increased density of brain (approximately 60%) and spinal cord (approximately 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 approximately 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 mu-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of mu-opioid receptors. Thus, mu-opioid antisense significantly reduced morphine potency without changing mu-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and mu-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of mu-opioid receptors does not involve changes in gene expression.
Shah
S
S
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
Duttaroy
A
A
Chen
B T
BT
Carroll
J
J
Yoburn
B C
BC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D015854:Up-Regulation / Q000187:drug effects*
D016376:Oligonucleotides, Antisense; D017450:Receptors, Opioid, mu; D009020:Morphine