Pentazocine inhibits norepinephrine transporter function by reducing its surface expression in bovine adrenal medullary cells.
(±)-Pentazocine (PTZ), a non-narcotic analgesic, is used for the clinical management of moderate to severe pain. To study the effect of PTZ on the descending noradrenergic inhibitory system, in the present study we examined the effect of [(3)H]norepinephrine (NE) uptake by cultured bovine adrenal medullary cells and human neuroblastoma SK-N-SH cells. (-)-PTZ and (+)-PTZ inhibited [(3)H]NE uptake by adrenal medullary cells in a concentration-dependent (3-100 μM) manner. Eadie-Hofstee analysis of [(3)H]NE uptake showed that both PTZs caused a significant decrease in the V(max) with little change in the apparent K(m), suggesting non-competitive inhibition. Nor-Binaltorphimine and BD-1047, κ-opioid and σ-receptor antagonists, respectively, did not affect the inhibition of [(3)H]NE uptake induced by (-)-PTZ and (+)-PTZ, respectively. PTZs suppressed specific [(3)H]nisoxetine binding to intact SK-N-SH cells, but not directly to the plasma membranes isolated from the bovine adrenal medulla. Scatchard analysis of [(3)H]nisoxetine binding to SK-N-SH cells revealed that PTZs reduced the B(max) without changing the apparent K(d). Western blot analysis showed a decrease in biotinylated cell-surface NE transporter (NET) expression after the treatment with (-)-PTZ. These findings suggest that PTZ inhibits the NET function by reducing the amount of NET in the cell surface membranes through an opioid and σ-receptor-independent pathway.
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Go
G
Obara
Yumiko
Y
Toyohira
Hirohide
H
Inagaki
Keita
K
Takahashi
Takafumi
T
Horishita
Takashi
T
Kawasaki
Susumu
S
Ueno
Masato
M
Tsutsui
Takeyoshi
T
Sata
Nobuyuki
N
Yanagihara
D000313:Adrenal Medulla / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005029:Ethylenediamines / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010423:Pentazocine / Q000494:pharmacology*; D011877:Radionuclide Imaging
D000701:Analgesics, Opioid; D005029:Ethylenediamines; D009292:Narcotic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D005473:Fluoxetine; C011386:nisoxetine; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C051844:norbinaltorphimine; D009271:Naltrexone; D010423:Pentazocine; D009638:Norepinephrine