Molecular components of tolerance to opiates in single hippocampal neurons.
We examined the effect of acute and chronic opioid treatment on synaptic transmission and mu-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-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), morphine, and methadone were all effective at blocking inhibitory transmission. These same drugs also reduced the amplitude of voltage-dependent Ca(2+) 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 beta-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.
Bushell
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Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA.
Endoh
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T
Simen
A A
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Ren
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Bindokas
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Miller
R J
RJ
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001464:Barium / Q000502:physiology; D002478:Cells, Cultured; D004361:Drug Tolerance / Q000502:physiology*; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D014018:Tissue Distribution; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605257:Arrb2 protein, rat; D019390:Arrestins; D009294:Narcotics; D018079:Receptors, GABA; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D001464:Barium