The μ-opioid receptor gene-dose dependent reductions in G-protein activation in the pons/medulla and antinociception induced by endomorphins in μ-opioid receptor knockout mice

H. Mizoguchi, M. Narita, D. E. Oji, C. Suganuma, H. Nagase, I. Sora, G. R. Uhl, E. Y. Cheng, L. F. Tseng

Research output: Contribution to journalArticlepeer-review

Abstract

There appear to be different relationships between μ-opioid receptor densities and the acute and neuroadaptive μ-opioid agonist-induced responses of the multiple opioid neuronal systems, including important pons/medulla circuits. The recent success in creating μ-opioid receptor knockout mice allows studies of μ-opioid agonist-induced pharmacological and physiological effects in animals that express no, one or two copies of the μ-opioid receptor gene. We now report that the binding of μ-opioid receptor ligand, [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin to membrane preparations of the pons/medulla was reduced by half in heterozygous μ-opioid receptor knockout mice and eliminated in homozygous μ-opioid receptor knockout mice. The endogenous μ-opioid agonist peptides endomorphin-1 and -2 activate G-proteins in the pons/medulla from wild-type mice in a concentration-dependent fashion, as assessed using [35S]guanosine-5'-o-(3-thio)triphosphate binding. This stimulation was reduced to half of the wild-type levels in heterozygous mice and eliminated in homozygous knockout mice. The intracerebroventricular injection of either endomorphin-1 or endomorphin-2 produced marked antinociception in the hot-plate and tail-flick tests in wild-type mice. These antinociceptive actions were significantly reduced in heterozygous μ-opioid receptor knockout mice, and virtually abolished in homozygous knockout mice. The μ-opioid receptors are the principal molecular targets for endomorphin-induced G-protein activation in the pons/medulla and the antinociception caused by the intracerebroventricular administration of μ-opioid agonists. These data support the notion that there are limited physiological μ-opioid receptor reserves for inducing G-protein activation in the pons/medulla and for the nociceptive modulation induced by the central administration of endomorphin-1 and -2.

Original languageEnglish (US)
Pages (from-to)203-207
Number of pages5
JournalNeuroscience
Volume94
Issue number1
DOIs
StatePublished - Sep 1999

Keywords

  • μ-opioid receptors
  • [S]GTPγS binding
  • Antinociception
  • Endomorphins
  • Knockout mice
  • Pons/medulla

ASJC Scopus subject areas

  • Neuroscience(all)

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