Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

Go Obara; Yumiko Toyohira; Hirohide Inagaki; Keita Takahashi; Takafumi Horishita; Takashi Kawasaki; Susumu Ueno; Masato Tsutsui; Takeyoshi Sata; Nobuyuki Yanagihara

doi:10.1254/jphs.12164FP

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Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

Go Obara, Yumiko Toyohira, Hirohide Inagaki, Keita Takahashi, Takafumi Horishita, Takashi Kawasaki, Susumu Ueno, Masato Tsutsui, Takeyoshi Sata, Nobuyuki Yanagihara

Author information

Go Obara
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Japan
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
Yumiko Toyohira
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
Hirohide Inagaki
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
Keita Takahashi
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
Takafumi Horishita
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Japan
Takashi Kawasaki
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Japan
Susumu Ueno
Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan
Masato Tsutsui
Department of Pharmacology, Graduate School of Medicine, University of The Ryukyus, Japan
Takeyoshi Sata
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Japan
Nobuyuki Yanagihara
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan

Keywords: adrenal medullary cell, descending noradrenergic inhibitory system, norepinephrine transporter, pentazocine, SK-N-SH cell

JOURNAL FREE ACCESS

2013 Volume 121 Issue 2 Pages 138-147

DOI https://doi.org/10.1254/jphs.12164FP

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Abstract

(±)-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 [³H]norepinephrine (NE) uptake by cultured bovine adrenal medullary cells and human neuroblastoma SK-N-SH cells. (−)-PTZ and (+)-PTZ inhibited [³H]NE uptake by adrenal medullary cells in a concentration-dependent (3 – 100 μM) manner. Eadie-Hofstee analysis of [³H]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 [³H]NE uptake induced by (−)-PTZ and (+)-PTZ, respectively. PTZs suppressed specific [³H]nisoxetine binding to intact SK-N-SH cells, but not directly to the plasma membranes isolated from the bovine adrenal medulla. Scatchard analysis of [³H]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.

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