Characterization of antinociception to opioid receptor selective agonists after antisense oligodeoxynucleotide-mediated "knock-down" of opioid receptors in vivo

Edward J. Bilsky, Robert N. Bernstein, Victor J. Hruby, Richard B. Rothman, Josephine Lai, Frank Porreca

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Pharmacological studies in vivo and in vitro have suggested the existence of subtypes of the delta opioid receptor termed delta1 and delta21 and δ2). The hypothesis of subtypes of ä receptors was further explored by assessing the effects of administration of antisense or mismatch oligodeoxynucleotides (ODN) in vivo to the cloned DOR, or to a conserved region of the cloned opioid receptors, on the antinociceptive responses elicited by selective μ, κ and opioid receptor agonists in mice. Additionally, the density of opioid δ receptors in brain after δ opioid receptor (DOR) ODN treatment was investigated. Repeated twice daily intracerebroventricular (i.c.v.) administration of DOR antisense, but not mismatch, ODN, produced a dose-and time-related blockade of i.c.v. [D-Ala2, Glu4]deltorphin (δ2 agonist), but not [D-Pen2, D-Pen5]enkephalin (δ1 agonist), antinociception. The antinociceptive responses to selective μ and κ opioid agonists were unaffected by DOR antisense or mismatch ODN treatments. The antinociceptive effect of an A90 dose of [D-Ala2, Glu4]deltorphin was significantly reduced by the third day of DOR antisense ODN administration and persisted over a treatment period of 6 days with recovery by the third posttreatment day. Saturation studies in mouse whole brain preparations with the selective δ-radioligand [3H]naltrindole showed that DOR antisense, but not mismatch, ODN treatment produced a significant time-related reduction in Bmax values of approximately 30 to 40% by day 6, without changing the Kd value. The reduction in DOR density was reversible and returned to control levels within 3 days after cessation of antisense ODN treatment. The i.c.v. administration of an antisense, but not mismatch, ODN directed to a conserved region of the cloned opioid receptors, termed common opioid receptor antisense ODN, inhibited the antinociceptive effects of i.c.v. μ, κ and δ agonists, including [D-Pen2, D-Pen5]enkephalin. These data further support the hypothesis of subtypes of opioid δ receptors.

Original languageEnglish (US)
Pages (from-to)491-501
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number1
StatePublished - Apr 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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