Molecular components of tolerance to opiates in single hippocampal neurons

T. Bushell, T. Endoh, A. A. Simen, D. Ren, V. P. Bindokas, R. J. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

We examined the effect of acute and chronic opioid treatment on synaptic transmission and μ-opioid receptor (MOR) endocytosis in cultures of naïve rat hippocampal neurons. Opioid agonists that activate MOR inhibited synaptic transmission at inhibitory but not excitatory autapses. [D-Ala2,N-Me-Phe4,Gly5ol]-enkephalin (DAMGO), morphine, and methadone were all effective at blocking inhibitory transmission. These same drugs also reduced the amplitude of voltage-dependent Ca2+ currents in inhibitory but not excitatory neurons. Chronic treatment with all three opioids reduced the subsequent effects of a challenge with either the same drug or one of the others in individual autaptic neurons. Chronic treatment with DAMGO or methadone produced internalization of enhanced yellow fluorescent protein-tagged MOR expressed in hippocampal neurons within hours, whereas morphine produced internalization much more slowly, even when accompanied by overexpression of β-arrestin-2. We conclude that DAMGO, methadone, and morphine all produce tolerance in single hippocampal neurons. Morphine-induced tolerance does not necessarily seem to involve receptor endocytosis.

Original languageEnglish (US)
Pages (from-to)55-64
Number of pages10
JournalMolecular pharmacology
Volume61
Issue number1
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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