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Molecular components of tolerance to opiates in single hippocampal neurons

Bushell, T. and Endoh, T. and Simen, A.A. and Ren, D. and Bindokas, V.P. and Miller, R.J. (2002) Molecular components of tolerance to opiates in single hippocampal neurons. Molecular Pharmacology, 61 (1). pp. 55-64. ISSN 0026-895X

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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,Gly5-ol]-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 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.