Methadone increases intracellular calcium in SH-SY5Y and SH-EP1-h[alpha]7 cells by activating neuronal nicotinic acetylcholine receptors

Jukka Pakkanen, Heli Nousiainen, Jari Yli-Kauhaluoma, Irene Kylänlahti, Tommi Möykkynen, Esa R Korpi, Jian-Hong Peng, Ronald Lukas, Liisa Ahtee, Raimo Tuominen

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

(-)-Methadone acts as an agonist at opioid receptors. Both (+)- and (-)-enantiomers of methadone have been suggested to be potent non-competitive antagonists of alpha 3 beta 4 neuronal nicotinic acetylcholine receptors (nAChRs). In the present study, we have examined interactions of methadone with nAChRs by using receptor binding assays, patch-clamp recording and calcium fluorometry imaging with SH-SY5Y cells naturally expressing alpha 7 and alpha 3* nAChR subtypes and SH-EP1-h alpha 7 cells heterologously expressing human alpha 7 nAChRs. Methadone potently inhibited binding of [H-3]methyllycaconitine to alpha 7 nAChRs and that of [H-3]epibatidine to alpha 3* nAChRs. Methadone pretreatment induced up-regulation of epibatidine binding sites in SH-SY5Y cells. Using whole-cell patch-clamp recording, both isomers of methadone activated cation currents via mecamylamine-sensitive nAChRs in SH-SY5Y cells. Nicotine and both (+)- and (-)-methadone evoked increases in [Ca2+](i) in both fluo-3AM loaded cell lines, and these effects were blocked by mecamylamine and by the alpha 7 selective antagonist methyllycaconitine, suggesting effects of methadone as alpha 7-nAChR agonist. Sensitivity of sustained nicotine and methadone effects to blockade by CdCl2, ryanodine and xestospongin-c implicates voltage-operated Ca2+ channels and intracellular Ca2+ stores as downstream modulators of elevated [Ca2+](i). Collectively, our results suggest that methadone engages in complex and potentially pharmacologically significant interactions with nAChRs.
Alkuperäiskielienglanti
LehtiJournal of Neurochemistry
Vuosikerta94
Numero5
Sivut1329-1341
Sivumäärä13
ISSN0022-3042
DOI - pysyväislinkit
TilaJulkaistu - 2005
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • nikotiini
  • metadoni
  • opiaatit
  • kalsium
  • riippuvuus
  • 317 Farmasia
  • 311 Peruslääketieteet

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