Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH3 pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH3 cells bathed in a high-K+, Ca2+-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K+ current (IK(erg)).Mtd suppressed the amplitude of IK(erg) in a concentration-dependent manner with an IC50 value of 10.4μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on IK(erg) was estimated with a dissociation constant of 8.2μM. Mtd tended to increase the rate of IK(erg) deactivation in a voltage-dependent fashion. EDDP (10μM) had no effect on IK(erg), while EMDP (10μM) slightly suppressed it. In GH3 cells incubated with naloxone (30μM), the Mtd-induced inhibition of IK(erg) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress IK(erg) in differentiated NG108-15 cells; dynorphin A1-13 did not reverse Mtd-induced inhibition of IK(erg).This study shows that Mtd has a depressant effect on IK(erg), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel.
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