Aya Matsui1, John T Williams. 1. Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Abstract
BACKGROUND AND PURPOSE: Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (K(IR) 3) channels. Methadone also blocks K(IR) 3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized. EXPERIMENTAL APPROACH: Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the activation of µ-opioid receptors and blockade of K(IR) 3 and NMDA channels with L- and D-methadone was examined. KEY RESULTS: The potency of L-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with D-methadone. A maximum hyperpolarization was caused by both enantiomers (∼30 mV); however, the maximum outward current measured with whole-cell voltage-clamp recording was smaller than the current induced by [Met](5) enkephalin. The K(IR) 3 conductance induced by activation of α(2) -adrenoceptors was decreased with high concentrations of L- and D-methadone (10-30 µM). In addition, methadone blocked the resting inward rectifying conductance (K(IR) ). Both L- and D-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted as a channel blocker. CONCLUSIONS AND IMPLICATIONS: Methadone activated µ-opioid receptors at low concentrations in a stereospecific manner. K(IR) 3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of µ-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone.
BACKGROUND AND PURPOSE:Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (K(IR) 3) channels. Methadone also blocks K(IR) 3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized. EXPERIMENTAL APPROACH: Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the activation of µ-opioid receptors and blockade of K(IR) 3 and NMDA channels with L- and D-methadone was examined. KEY RESULTS: The potency of L-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with D-methadone. A maximum hyperpolarization was caused by both enantiomers (∼30 mV); however, the maximum outward current measured with whole-cell voltage-clamp recording was smaller than the current induced by [Met](5) enkephalin. The K(IR) 3 conductance induced by activation of α(2) -adrenoceptors was decreased with high concentrations of L- and D-methadone (10-30 µM). In addition, methadone blocked the resting inward rectifying conductance (K(IR) ). Both L- and D-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted as a channel blocker. CONCLUSIONS AND IMPLICATIONS: Methadone activated µ-opioid receptors at low concentrations in a stereospecific manner. K(IR) 3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of µ-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone.
Authors: John T Williams; Susan L Ingram; Graeme Henderson; Charles Chavkin; Mark von Zastrow; Stefan Schulz; Thomas Koch; Christopher J Evans; Macdonald J Christie Journal: Pharmacol Rev Date: 2013-01-15 Impact factor: 25.468