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Br J Pharmacol. 2010 Nov;161(6):1403-13. doi: 10.1111/j.1476-5381.2010.00967.x.

Activation of µ-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus.

Author information

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.

PMID:
20659105
PMCID:
PMC3000663
DOI:
10.1111/j.1476-5381.2010.00967.x
[Indexed for MEDLINE]
Free PMC Article

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