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

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Pentazocine Inhibits Norepinephrine Transporter Function by Reducing Its Surface Expression in Bovine Adrenal Medullary Cells J Pharmacol Sci 121, 138 – 147 (2013) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Full Paper Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells Go Obara1,2, Yumiko Toyohira2, Hirohide Inagaki2, Keita Takahashi2, Takafumi Horishita1, Takashi Kawasaki1, Susumu Ueno3, Masato Tsutsui4, Takeyoshi Sata1, and Nobuyuki Yanagihara2,* 1Department of Anesthesiology, School of Medicine, 2Department of Pharmacology, School of Medicine, 3Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 870-8555, Japan 4Department of Pharmacology, Graduate School of Medicine, University of The Ryukyus, Okinawa 903-0215, Japan Received July 23, 2012; Accepted December 12, 2012 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 Vmax with little change in the apparent Km, 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 Bmax without changing the apparent Kd. 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. Keywords: adrenal medullary cell, descending noradrenergic inhibitory system, norepinephrine transporter, pentazocine, SK-N-SH cell Introduction are desired. For example, physicians are often reluctant to prescribe opioids for a chronic pain condition because The racemic compound (±)-pentazocine (PTZ), a of concerns about the potential for abuse and tolerance non-narcotic analgesic, is used for the management of development. Additionally, opioids are of questionable moderate to severe pain in humans. (−)-PTZ is known to effectiveness in treating some pain conditions such as act as an opioid analgesic, and (+)-PTZ is a σ-receptor neuropathic pain (2). agonist without analgesic effects. The antinociceptive Analgesia can alternatively be affected through modu- effects of (−)-PTZ have been reported to be mediated by lation of monoamine activity with serotonin (5-HT) or its agonist action at the κ-opioid receptor (1). Although norepinephrine (NE) uptake inhibitors such as amitripty- opioids remain the standard analgesics, there are clinical line or desipramine (3, 4). These agents are often more situations in which alternative approaches to analgesia effective than opioid analgesics in treating neuropathic pain (5) and are not usually associated with abuse poten- *Corresponding author. [email protected] tial. Furthermore, compounds that modify monoamine Published online in J-STAGE on February 1, 2013 (in advance) levels have been reported to modulate opioid-induced doi: 10.1254/jphs.12164FP analgesia (6 – 8). In some paradigms, the interactions 138 Inhibition of NET by Pentazocine 139 between opioid drugs and monoamine uptake inhibitors naloxone hydrochloride dehydrate, calphostin C, and have been reported as additive, whereas in other models chelerythrine (Sigma, St. Louis, MO, USA); nisoxetine the interactions are synergistic (9, 10). hydrochloride (Research Biochemicals International, The NE transporter (NET) is selectively expressed Natick, MA, USA); nor-Binaltorphimine dihydrochloride on NE nerve terminals, where it can exert spatial and and GF109203X (Wako, Osaka); BD-1047 dihydrobro- temporal control over the action of NE (11 – 13). NET mide (Tocris Bioscience, Bristol, JK, USA); biotin induces the termination of neurotransmission by the sucinimidyl ester (sulfo-NHS-biotin), MagnaBindTM reuptake of NE released into the extracellular milieu. Streptavidin Beads (Thermo Scientific, Barrington, IL, 3 Human NET, which belongs to the gene family USA); L-[7,8- H]NE, hydroxytryptamine creatinine (SLC6A2) of sodium- and chloride-dependent neuro- sulfate, 5-[1,2-3H(N)], [N-methyl-3H]nisoxetine hydro- transmitter transporters (12, 14, 15), was the first chloride (Perkin-Elmer Life Sciences, Boston, MA, 45 monoamine transporter to be cloned, and its mRNA is USA); and CaCl2 (GE Health Care UK Ltd., Little abundantly localized in the brain stem and adrenal Chalfont, Buckinghamshire, UK). medulla (11). NET is also a critical target for various Adrenal medullary cells were isolated by collagenase antidepressant and psychostimulants that interact with digestion of slices of bovine adrenal medulla. The cells NET to increase extracellular NE by inhibiting NE were maintained in a monolayer culture at a density of uptake (11 – 13). 1 × 106 cells per well (24-well plate; Corning Life Adrenal medullary cells derived from the embryonic Sciences, Lowell, MA, USA) in culture medium (Eagle’s neural crest share many physiological and pharmaco- MEM) with 10% calf serum and several antibiotics in logical properties with postganglionic sympathetic neurons. 5% CO2 / 95% air (24) . In some experiments, the human The cells express functional NET proteins (16 – 18). The noradrenergic neuroblastoma cell line, SK-N-SH pharmacological properties of NET in bovine adrenal (RCB0424), provided by the RIKEN Cell Bank (Tsukuba), medullary cells are similar to those of NET in central and was used. SK-N-SH cells were maintained in culture peripheral noradrenergic neurons (13). Therefore, NET medium containing α-MEM supplemented with 10% in bovine adrenal medullary cells has provided a conve- fetal bovine serum, and several antibiotics. Cells were nient model for studying the effects of various agents plated on poly-L-lysine–coated plates at a density of 6 such as anesthetics and antipsychotic drugs on this 0.3 × 10 cells per well in 5% CO2 / 95% air. transporter (19, 20). Some centrally acting analgesic [3H]NE uptake by the cells was performed as follows: agents such as tramadol have both opioid and monoamine Cultured bovine adrenal medullary cells (1 × 106 / well) modes of action (21, 22). Tramadol inhibits NET func- or SK-N-SH cells (0.3 × 106 / well) were preincubated tion by blocking desipramine-binding sites as the basis with or without PTZ for the indicated times and further for its antinociceptive effect (19). Another opioid analgesic, incubated at 37°C for another 12 min in KRH buffer PTZ, has preliminarily been reported to inhibit the uptake containing 100 μM pargyline, 1 mM ascorbic acid, and of NE in the rat brain cortex (23), but the precise mecha- [3H]NE (500 or 100 nM, respectively, 0.1 μCi) in the nism remains unclear. In the present study, we investi- presence or absence of desipramine and PTZ. KRH gated the effect of PTZ on NET activity in cultured buffer was composed of 154 mM NaCl, 5.6 mM KCl, 1.1 bovine adrenal medullary cells and SK-N-SH cells and mM MgSO4, 2.2 mM CaCl2, 10 mM HEPES-Tris, and 10 found that PTZ inhibits NET activity through suppres- mM glucose, adjusted to pH 7.4. After incubation, the sion of its cell surface expression in an opioid receptor– cells were rapidly washed three times with 250 μl of and σ-receptor–independent manner. ice-cold KRH buffer and solubilized in 500 μl of 10% Triton X-100. The radioactivity in the solubilized cells Materials and Methods was counted with a liquid scintillation counter (Trib-Carb 2900TR; Packard BioScience, Meriden, CT, USA). Drugs and reagents were obtained from the following Desipramine-sensitive uptake was calculated by sub- sources: Eagle’s minimum essential medium (Eagle’s tracting the value obtained in the presence of 10 μM MEM) (Nissui Pharmaceutical, Tokyo); α-MEM, desipramine from that obtained in the absence of Dulbecco’s Modified Eagle’s medium (DMEM), l-NE, desipramine (25). In some experiments to determine pargyline hydrochloride, and ascorbic acid (Nacalai Tesque, kinetic parameters, cells were preincubated with or Kyoto); collagenase (Nitta Zerachin, Osaka); calf serum without PTZ (30 μM) for 20 min and then further incu- (Cell Culture Technologies, Gravesano, Switzerland); bated in the presence of [3H]NE (1 – 30 μM) with or fetal bovine serum (SAFC Biosciences, Inc., Lenexa, KS, without PTZ for 12 min. The apparent Michaelis constant USA); (−)-PTZ, (+)-PTZ, 5-hydroxytryptamine (5-HT), (Km) and the maximal velocity (Vmax) for initial rates of desipramine hydrochloride, clomipramine hydrochloride, [3H]NE uptake were determined by the Eadie-Hofstee 140 G Obara et al analysis and calculated by non-linear regression analysis fractions were separated by SDS-PAGE (10%), and were of the data for each individual experiment, using electroblotted onto polyvinylidene difluoride (PVDF) GraphPad Prism
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