The contribution of MOR-1 exons 1-4 to morphine and heroin analgesia and dependence

Neurosci Lett. 2009 Jul 3;457(3):115-9. doi: 10.1016/j.neulet.2009.04.012. Epub 2009 Apr 9.

Abstract

Although morphine and heroin analgesia is mediated by mu-opioid receptors encoded by the MOR-1 gene, distinct isoforms are involved. Both opioids also induce dependence by acting at mu-opioid receptors, but which variants are utilized is not known. Here, we assayed morphine and heroin analgesia and dependence in mice treated with antisense oligodeoxynucleotides (AO) targeting MOR-1 exons 1-4. Whereas AOs targeting exons 1 and 4 blocked morphine analgesia, those targeting exons 2 and 3 blocked heroin analgesia. Neither morphine nor heroin analgesia was compromised 5 days after the last AO injection. In morphine and heroin dependent mice, only exon 1 AO significantly reduced jumping incidence during naloxone (50mg/kg) precipitated withdrawal. Neither analgesia nor withdrawal jumping was attenuated in controls pretreated with saline or a mismatch oligodeoxynucleotide control sequence. While these data confirm previous reports that morphine and heroin analgesia are not mediated by a single mu-opioid receptor, both opiates nonetheless apparently induce dependence via a mu-opioid receptor isoform containing exon 1. For heroin, the possibility that analgesia and dependence are mediated by distinct mu-opioid receptor isoforms offers the prospect of developing potent opiate analgesics possessing reduced dependence liability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia*
  • Analgesics, Opioid / toxicity
  • Analysis of Variance
  • Animals
  • Exons
  • Heroin / toxicity
  • Heroin Dependence / genetics*
  • Hot Temperature
  • Male
  • Mice
  • Morphine / toxicity
  • Morphine Dependence / genetics*
  • Motor Activity / drug effects
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Oligonucleotides, Antisense / metabolism
  • Pain Measurement
  • Protein Isoforms
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism
  • Substance Withdrawal Syndrome

Substances

  • Analgesics, Opioid
  • Narcotic Antagonists
  • Oligonucleotides, Antisense
  • Oprm protein, mouse
  • Protein Isoforms
  • Receptors, Opioid, mu
  • Naloxone
  • Heroin
  • Morphine