Activation of μ-opioid receptors and block of K IR3 potassium channels and NMDA receptor conductance by l- and d-methadone in rat locus coeruleus

Aya Matsui, John T. Williams

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


BACKGROUND AND PURPOSE Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (K IR3) channels. Methadone also blocks K IR3 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 IR3 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] 5enkephalin. The K IR3 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 IR3 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.

Original languageEnglish (US)
Pages (from-to)1403-1413
Number of pages11
JournalBritish Journal of Pharmacology
Issue number6
StatePublished - Nov 2010


  • K 3
  • NMDA
  • Potassium channels
  • Stereospecificity
  • l-and d-methadone
  • μ-opioid receptor

ASJC Scopus subject areas

  • Pharmacology


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