TY - JOUR T1 - Molecular Components of Tolerance to Opiates in Single Hippocampal Neurons JF - Molecular Pharmacology JO - Mol Pharmacol SP - 55 LP - 64 DO - 10.1124/mol.61.1.55 VL - 61 IS - 1 AU - T. Bushell AU - T. Endoh AU - A. A. Simen AU - D. Ren AU - V. P. Bindokas AU - R. J. Miller Y1 - 2002/01/01 UR - http://molpharm.aspetjournals.org/content/61/1/55.abstract N2 - We examined the effect of acute and chronic opioid treatment on synaptic transmission and μ-opioid receptor (MOR) endocytosis in cultures of naı̈ve 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 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. ER -