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ANESTHETIC PHARMACOLOGY

Tramadol Inhibits Norepinephrine Transporter Function at Desipramine-Binding Sites in Cultured Bovine Adrenal Medullary Cells

Kenichiro Sagata, MD^*, Kouichiro Minami, MD, PhD^*, Nobuyuki Yanagihara, PhD, Munehiro Shiraishi, MD^*, Yumiko Toyohira, PhD, Susumu Ueno, MD, PhD, and Akio Shigematsu, MD, PhD^*

Departments of *Anesthesiology and Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

Address correspondence and reprint requests to Kouichiro Minami, Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan. Address e-mail to kminami{at}med.uoeh-u.ac.jp

Tramadol is a widely used analgesic, but its mode of action is not well understood. To study the effects of tramadol on norepinephrine transporter (NET) function, we assayed the effect of tramadol on [³H]-norepinephrine ([³H]-NE) uptake and [³H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We then characterized [¹⁴C]-tramadol binding in cultured bovine adrenal medullary cells. Tramadol inhibited the desipramine-sensitive uptake of [³H]-NE by the cells in a concentration-dependent manner (50% inhibitory concentration = 21.5 ± 6.0 µM). Saturation analysis revealed that tramadol increased the apparent Michaelis constant of [³H]-NE uptake without changing the maximal velocity, indicating that inhibition occurred via competition for the NET (inhibition constant, K_i = 13.7 µM). Tramadol inhibited the specific binding of [³H]-desipramine to plasma membranes. Scatchard analysis of [³H]-desipramine binding revealed that tramadol increased the apparent dissociation constant (K_d) for binding without altering maximal binding, indicating competitive inhibition (K_i = 11.2 µM). The binding of [¹⁴C]-tramadol to the cells was specific and saturable, with a K_d of 18.1 ± 2.4 µM. These findings indicate that tramadol competitively inhibits NET function at desipramine-binding sites.

IMPLICATIONS: Tramadol competitively inhibits norepinephrine transporter function at desipramine-binding sites in the adrenal medullary cells and probably the noradrenergic neurons of the descending inhibitory system.

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