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The Antihyperalgesic Effects of Intrathecal Bupropion, a Dopamine and Noradrenaline Reuptake Inhibitor, in a Rat Model of Neuropathic Pain

Hoshino, Hajime MD; Obata, Hideaki MD, PhD; Nakajima, Kunie MD, PhD; Mieda, Rie MD; Saito, Shigeru MD, PhD

doi: 10.1213/ANE.0000000000000540
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: Antidepressants are often used for the treatment of neuropathic pain, and their analgesic effects rely on increased noradrenaline and serotonin levels in the spinal cord. Clinical studies have also shown that bupropion, a dopamine and noradrenaline reuptake inhibitor, has strong efficacy in neuropathic pain; however, the role of spinal cord dopamine in neuropathic pain is unknown. We hypothesized that bupropion inhibits neuropathic pain by increasing noradrenaline and dopamine in the spinal cord. In the present study, we determined the efficacy and underlying mechanisms of intrathecal administration of bupropion in a rat model of neuropathic pain.

METHODS: Male Sprague-Dawley rats were anesthetized, and right L5 spinal nerve ligation (SNL) was performed to produce mechanical hyperalgesia of the hindpaw. Withdrawal threshold to a paw pressure test was measured before and after intrathecal administration of bupropion, without or with intrathecal antagonists for α2-adrenoceptors and dopamine D2 receptors. In vivo microdialysis was performed in the dorsal horn of the lumbar spinal cord to measure noradrenaline and dopamine concentrations after intrathecal injection of bupropion. We also measured the noradrenaline and dopamine contents in the ipsilateral dorsal lumbar spinal cord in normal rats and in rats 2, 3, and 4 weeks after SNL.

RESULTS: Intrathecal injection of bupropion produced a dose-dependent antihyperalgesic effect (3, 10, 30, and 100 μg, P < 0.001). The effect (30 μg) was dose-dependently reversed by intrathecal pretreatment (15 minutes before bupropion injection) with the α2-adrenoceptor antagonist idazoxan (3, 10, and 30 μg, P < 0.001) and D2 receptor antagonist sulpiride (3, 10, and 30 μg, P < 0.001). Microdialysis revealed that noradrenaline and dopamine concentrations in the spinal dorsal horn were increased after intrathecal injection of bupropion (30 μg, P < 0.001 and P = 0.001, respectively). Furthermore, the noradrenaline and dopamine contents in the spinal dorsal horn were increased 2 weeks after SNL (P < 0.001 and P = 0.044, respectively) and then decreased gradually.

CONCLUSIONS: These findings suggest that plasticity of descending inhibitory pathways such as the noradrenaline and dopamine systems contributes to the maintenance of neuropathic pain and that spinal cord noradrenaline and dopamine both play an inhibitory role in neuropathic pain.

Published ahead of print November 25, 2014.

From the Department of Anesthesiology, Gunma University Graduate School of Medicine, Gunma, Japan.

Accepted for publication September 26, 2014.

Published ahead of print November 25, 2014.

Funding: This work was supported by Grants-in-Aid for Scientific Research (grant number 20591823 to HO, 42791578 to RM, and 24791581 to KN) from the Ministry of Education, Culture, Sport, Science, and Technology of Japan (Tokyo, Japan).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Hideaki Obata, MD, PhD, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showa, Maebashi, Gunma 371-8511, Japan. Address e-mail to hobata@gunma-u.ac.jp.

Peripheral nerve injury leads to neuropathic pain, which is associated with various changes in sensory processing from the primary afferent neurons to the spinal cord and on to supraspinal and cortical regions. Brainstem-spinal descending inhibitory pathways, including noradrenergic neurons, suppress nociceptive signals from primary afferent neurons to the spinal dorsal horn.1 Antidepressants such as tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors are thus recommended as first-line drugs for the treatment of neuropathic pain,2 as a recent study showed that increased noradrenaline levels in the spinal cord underlie the therapeutic effect of antidepressants in neuropathic pain.3

Dopamine also plays a crucial role in nociceptive transmission in the central nervous system.4 Animal studies have shown that in the brain the dopaminergic system is involved in pain modulation5,6 and that dopamine receptor agonists predominantly suppress pain-related responses via dopamine D2 receptors.7,8 Furthermore, focal electrical stimulation of the A11 area in the brain suppresses the nociceptive responses of spinal dorsal horn neurons.9 These findings suggest that activation of descending dopaminergic pathways and subsequent release of dopamine in the spinal cord play an important role in the control of nociceptive transmission. However, the role of spinal cord dopamine in neuropathic pain is not clear.

Bupropion is a noradrenaline and dopamine reuptake inhibitor that has been reported to show strong efficacy against neuropathic pain.10,11 We hypothesized that bupropion suppresses neuropathic pain by increasing noradrenaline and dopamine levels in the spinal cord. To test this hypothesis, we examined the efficacy and mechanisms of the antihyperalgesic effects of intrathecally administered bupropion using a rat model of neuropathic pain produced by spinal nerve ligation (SNL). Because previous studies have suggested that the descending noradrenergic system shows plastic changes after nerve injury,3,12,13 we also examined the change of noradrenaline and dopamine levels in the lumbar spinal cord over time after SNL.

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METHODS

Surgical Preparation

The experiments were approved by the Animal Care and Use Committee of the Gunma University Graduate School of Medicine. Adult male Sprague-Dawley rats (250 g) were used (99 rats). The animals were housed on soft bedding in a temperature-controlled environment under a 12-hour light-dark cycle with free access to food and water. The animals were allowed to habituate to the housing facilities before surgery or behavioral testing.

SNL was performed as previously described.14 In brief, animals were anesthetized with isoflurane (2%) in oxygen, and the right L5 spinal nerve was tightly ligated with 5-0 silk and cut just distal to the ligature. The wound was then closed. Ten days after SNL surgery, an intrathecal catheter was inserted for drug administration. A sterilized 32-gauge polyethylene catheter (RecathCo, Allison Park, PA) connected to 8.5 cm of Tygon external tubing (Saint-Gobain Performance Plastics, Akron, OH) was inserted through the cisterna magna while the rat was under isoflurane anesthesia, as previously described.15 The catheter was passed caudally 7.5 to 8.0 cm from the cisterna magna to the lumbar enlargement. The animals were allowed to recover for 7 days before drug testing.

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Behavioral Testing

The withdrawal threshold to pressure applied to the hindpaw, expressed in grams, was measured using an analgesimeter (Ugo Basile, Comerio, Italy), as previously described.16 In brief, the analgesimeter device is used to apply increasing pressure to the hindpaw. When the animal withdraws its paw, the pressure is immediately released, and the withdrawal threshold is output in grams. A cutoff of 250 g was used to avoid tissue injury. Animal training with the analgesimeter was performed 3 times to familiarize the animals to the test before drug treatment.

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Drug Testing and Their Administration

The first series of experiments was performed to examine the time course and dose response of the antihyperalgesic effects of intrathecally administered bupropion (0, 3, 10, 30, and 100 μg). The withdrawal thresholds were determined before (before SNL surgery), at 0 (before drug injection), 15, 30, and 60 minutes after injection, and then at 60-minute intervals until 480 minutes after injection. The second series of experiments was performed to determine the effects of intrathecal pretreatment with the α2-adrenoceptor antagonist idazoxan or the dopamine D2 receptor antagonist sulpiride. Each antagonist (0, 3, 10, and 30 μg) was administered intrathecally 15 minutes before bupropion (30 μg) injection. Adverse behavioral effects, such as sedation or agitation, were carefully observed and graded as 0 (normal), 1 (moderate), or 2 (severe). Motor function was assessed in terms of the placing reflex and righting reflex with scores of 0 (normal), 1 (impaired), or 2 (absent). To evaluate the placing reflex, the hind limbs of the rat were held and the dorsal surface of the hindpaws was brought into contact with the edge of a table. The experimenter recorded whether the hindpaws were placed on the surface reflexively. To evaluate the righting reflex, the rat was placed on its back on a flat surface and the experimenter noted whether it immediately assumed the normal upright position. Drug tests were performed 17 to 22 days after SNL surgery. To reduce the number of animals, we used the rats 2 times at 2- to 3-day intervals. The experimenter performing the behavioral test was blinded to the drug treatment and dose.

For intrathecal injection, bupropion and idazoxan were dissolved in saline, and sulpiride was dissolved in a mixture of 67% dimethylsulfoxide and 33% saline. The drugs were injected intrathecally in a volume of 5 μL, followed by a 15-μL injection of saline to flush the catheter. Bupropion and idazoxan were purchased from Sigma (St. Louis, MO), and sulpiride was purchased from Tocris (Ellisville, MO).

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Microdialysis

Microdialysis was performed as previously described.17 Anesthesia was induced with 3% isoflurane and maintained with 1.5% isoflurane in 100% oxygen through a nose cone. The left femoral vein was cannulated for fluid infusion. The rectal temperature was maintained at 37°C to 38°C with a heating pad placed beneath the animal. The L3-6 level of the right spinal cord was exposed by thoracolumbar laminectomy, and then the rat was placed in a stereotaxic apparatus. After the dura was punctured with a 30-gauge needle, the microdialysis probe (outer diameter = 0.22 mm, inner diameter = 0.20 mm, length = 1 mm; A-I-8-01; Eicom Co., Kyoto, Japan) was inserted from just lateral to the dorsal root and advanced at an angle of 15° to 30° to a depth of 1 mm using a micromanipulator (model WR-88; Narishige, Tokyo, Japan). The microdialysis probe was perfused with Ringer’s solution (147 mmol/L NaCl, 4 mmol/L KCl, and 2.3 mmol/L CaCl2) at a constant flow rate (1 μL/min) using a microsyringe pump (ESP-64; Eicom Co.). After 120 minutes of constant perfusion, 2 consecutive samples were collected to determine basal noradrenaline and dopamine concentrations in the dialysate (baseline). The effective dose of bupropion (30 μg) or saline (5 μL) was administered through the intrathecal catheter, and 15-minute perfusate fractions were collected into an auto injector (EAS-20; Eicom Co.). The noradrenaline and dopamine concentrations in the perfusate were analyzed using high-performance liquid chromatography with electrochemical detection using an HTEC-500 analyzing system (Eicom Co.). The chromatographic conditions were as follows: The mobile phase comprised 0.1 mol/L ammonium acetate buffer (pH 6.0), 0.05 mol/L sodium sulfonate in methanol (7:3 vol/vol), and 50 mg/L Na2-EDTA, and the column was an EICOMPAC CAX (2.0 mm × 200 mm; Eicom Co.). The working electrode was glassy carbon (WE-3G; Eicom Co.) with a flow rate of 0.25 mL/min. The detector voltage was set to 0.45 V. The detector temperature was set to 35.0°C. The retention time for noradrenaline and dopamine was 5.4 minutes and 7.1 minutes, respectively.

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Noradrenaline and Dopamine Contents in the Spinal Cord

We also measured the noradrenaline and dopamine contents in the spinal dorsal horn in normal and SNL rats at 2, 3, and 4 weeks after SNL surgery. To isolate the dorsal horn of the spinal cord, the portion corresponding to segments L4-6 was divided into 4 constituent quadrants: dorsal right, dorsal left, ventral right, and ventral left. The dorsal right (ligation side) portion of the spinal cord was weighed and homogenized in 500 μL of 0.2 mol/L perchloric acid containing 0.1 mmol/L Na2-EDTA and isoproterenol (0.02 mg/mL) as an internal standard, and centrifuged at 20,000g at 0°C for 15 minutes. The supernatants were adjusted to pH 3.0 by adding 1 mol/L sodium acetate and then filtered through a centrifugal filter with a pore size of 0.45 μm (Millipore, Bedford, MA). Samples (10 μL) were injected into an HTEC-500 analyzing system (Eicom Co.), and the concentrations of noradrenaline and dopamine were analyzed using high-performance liquid chromatography with electrochemical detection. The chromatographic conditions were as follows: The mobile phase comprised 0.1 mol/L phosphate buffer (pH 6.0) containing 5 mg/L Na2-EDTA, 190 mg/L sodium 1-octanesulfate acid, and 17% methanol, and the column was an EICOMPAK SC-5ODS (3.0 × 150 mm; Eicom Co.). The working electrode was glassy carbon (WE-3G; Eicom Co.), with a flow rate of 0.5 mL/min. The detector voltage was set at 0.75 V. The detector temperature was set at 35.0°C. The retention time for noradrenaline and dopamine was 4.43 minutes and 9.56 minutes, respectively.

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Statistical Analysis

We selected a minimal sample size of 6 based on our previous study.18 The data are presented as the mean ± SEM. The effects of the drug treatments on withdrawal thresholds in the behavioral studies and on spinal cord noradrenaline and dopamine levels in the microdialysis studies were analyzed using 2-way repeated-measures analyses of variance (ANOVA), followed by the Student t test with Bonferroni correction for dose-response analysis. Independent analyses were performed for each time point by the Student t test and report P values that are Bonferroni corrected; differences between time points were not compared statistically. The change in the noradrenaline and dopamine contents in the spinal cord over time after SNL, with the level in normal (control) rats included as a representative baseline, was evaluated using a 1-way ANOVA, followed by the Student t test and report P values that are Dunnett corrected because the focus of the analysis was the change in the injured animals at 2, 3, and 4 weeks after SNL surgery. Before ANOVA, the data were first assessed for normality (Shapiro-Wilk test) and equal variance (F test). Because some data from the behavioral studies did not pass these tests, a conservative approach was chosen for the behavioral studies; P < 0.01 was defined as statistically significant. The residuals of each of the other 4 ANOVA models followed normal distributions (all 4 P > 0.251) and maintained equality of variance (all 4 P > 0.284); therefore, P < 0.05 was defined as statistically significant. The statistical analysis was conducted using SigmaPlot 12 (Systat Software Inc., San Jose, CA).

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RESULTS

Antihyperalgesic Effects of Bupropion

Intrathecal injection of bupropion (3, 10, 30, and 100 μg) produced dose-dependent antihyperalgesic effects (F4,275 = 36.77, P < 0.001 by 2-way repeated-measures ANOVA followed by the Student t test with Bonferroni correction); the effect was observed at 15 minutes and continued to 480 minutes after injection of the 100-μg dose, which was the end of the measurement period in the experiment (Bonferroni-adjusted P = 0.007 and 0.001, respectively; Fig. 1). No adverse behavioral effects, such as sedation or agitation, were observed, and the placing reflex and righting reflex were normal (the score was 0 in all rats). Intrathecal pretreatment with idazoxan, an α2-adrenoceptor antagonist (3, 10, and 30 μg), dose-dependently reversed the antihyperalgesic effect of bupropion (30 μg) (F5,240 = 28.82, P < 0.001 by 2-way repeated-measures ANOVA followed by the Student t test with Bonferroni correction). The maximal dose of idazoxan by itself (30 μg) did not alter withdrawal thresholds compared with the saline group (Fig. 2A). Intrathecal pretreatment with sulpiride, a dopamine D2 receptor antagonist (3, 10, and 30 μg), dose-dependently reversed the antihyperalgesic effect of bupropion (30 μg) (F5,240 = 17.01, P < 0.001 by 2-way repeated-measures ANOVA followed by the Student t test with Bonferroni correction). The maximal dose of bupropion itself (30 μg) did not alter withdrawal thresholds compared with the saline group (Fig. 2B).

Figure 1

Figure 1

Figure 2

Figure 2

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Increased Noradrenaline and Dopamine Levels in the Spinal Cord After Injection of Bupropion Revealed by Microdialysis

Figure 3 shows the time course of the change of the noradrenaline and dopamine concentrations in the dorsal horn of the spinal cord in SNL rats after bupropion injection. The baseline noradrenaline and dopamine concentrations before bupropion injection were 2.48 ± 0.38 pg/15 μL and 0.89 ± 0.19 pg/15 μL, respectively (n = 6). After intrathecal injection of bupropion (30 μg), the concentrations of both noradrenaline and dopamine were increased (F1,60 = 37.14, P < 0.001 and F1,60 = 19.55, P = 0.001, respectively, by 2-way repeated-measures ANOVA). The noradrenaline concentration increased within 15 minutes (Bonferroni-adjusted P = 0.013), and the increase continued for >90 minutes (Bonferroni-adjusted P < 0.001) compared with the saline-treated group. The concentration of dopamine also increased within 15 minutes (Bonferroni-adjusted P = 0.023), and the increase was maintained at 45 minutes after injection (Bonferroni-adjusted P < 0.001).

Figure 3

Figure 3

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Noradrenaline and Dopamine Contents in the Spinal Cord of Normal and SNL Rats

The noradrenaline and dopamine contents in homogenized tissue from the ipsilateral dorsal spinal cord of normal rats (control) and SNL rats were also determined (Fig. 4). The noradrenaline concentration in SNL rats 2 weeks after nerve ligation was higher (1617.5 ± 104.0 pg/g, n = 6) than that in normal rats (1196.3 ± 117.6 pg/g, n = 6, F3,20 = 64.55, P < 0.001 by 1-way ANOVA, Dunnett-adjusted P < 0.001). However, the noradrenaline concentration in SNL rats 3 weeks (925.6 ± 49.9 pg/g) and 4 weeks (1037.5 ± 100.3 pg/g, n = 6) after ligation was decreased compared with that in normal rats (Dunnett-adjusted P < 0.001 and P = 0.023, respectively).

Figure 4

Figure 4

At 2 weeks after SNL, an increase in the dopamine concentration in the ipsilateral dorsal spinal cord (220.7± 33.8 pg/g, n = 6) was observed relative to normal rats (142.9 ± 23.9 pg/g, n = 6, F3,20 = 3.593, P = 0.032 by 1-way ANOVA, Dunnett-adjusted P = 0.044), and the dopamine concentration subsequently returned to a level similar to that in normal rats.

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DISCUSSION

Bupropion is a dopamine-noradrenaline reuptake inhibitor whose acute administration decreases the reuptake of dopamine and noradrenaline into synaptosomes,19 reduces the firing rate of central noradrenaline- and dopamine-containing neurons,20 and increases extracellular striatal dopamine levels.21 We hypothesized that intrathecal administration of bupropion would suppress neuropathic pain symptoms through increased noradrenaline and dopamine levels in the spinal cord. We found that intrathecal administration of bupropion indeed produced dose-dependent antihyperalgesia through increased noradrenaline and dopamine levels in the spinal cord, with the effects mediated by spinal α2-adrenoceptors and dopamine D2 receptors. Furthermore, the antihyperalgesic effect of the maximal dose of bupropion (100 μg) continued for >8 hours without any adverse effects.

We recently demonstrated that increased noradrenaline levels in the spinal cord play a critical role in the inhibitory effect of antidepressants on neuropathic pain symptoms.3 Previous studies demonstrated increased potency and efficacy of intrathecal injection of α2-adrenoceptor agonists such as dexmedetomidine and clonidine, which mimic the effects of spinally released noradrenaline, in neuropathic pain states.18,22 These pharmacologic effects in neuropathic pain may be associated with spinal cord plasticity because animal models of neuropathic pain have shown increased expression of inhibitory α2-adrenoceptors in C-fibers,23 increased G protein coupling of spinal α2-adrenoceptors,24 and increased α2-adrenoceptor–mediated activation of inhibitory cholinergic interneurons.18,25 Consistent with these reports, intrathecal injection of bupropion in the present study attenuated SNL-induced hyperalgesia, and the effect was dose-dependently reversed by idazoxan, an α2-adrenoceptor antagonist. In the microdialysis studies, noradrenaline levels were increased in the dorsal horn of the spinal cord after intrathecal bupropion injection. These results indicate that the antihyperalgesic effect of bupropion depends on increased noradrenaline levels in the spinal cord.

Dopamine plays an important role in nociceptive transmission, and several reports have described direct analgesic actions of dopamine in regions of the brain, such as the striatum,7,26 the basal ganglia,27 and the nucleus accumbens.8,28 Dopamine also plays a critical role in nociceptive transmission in the spinal cord through descending inputs from the brain, as a previous study reported that no dopaminergic cell bodies are present in the spinal cord.29 Electrophysiologic studies have shown that focal electrical stimulation of the A11 area of the brain suppresses the nociceptive responses of neurons in the dorsal horn of the spinal cord.9 Furthermore, an in vivo patch clamp analysis revealed that dopamine suppressed the synaptic response to noxious stimuli in substantia gelatinosa neurons in the spinal cord.30 Behavioral studies have also demonstrated that intrathecal administration of a dopamine agonist has thermal antinociceptive effects.31,32

Previous studies have shown that dopamine D2 receptors in the brain contribute to dopamine-induced analgesia for pathologic pain such as inflammatory pain7,8,33 and neuropathic pain.26 D2 receptors are also involved in dopaminergic suppression of nociceptive transmission in the spinal dorsal horn.30 Therefore, we speculate that D2 receptors in the spinal dorsal horn are involved in the attenuation of not only acute nociception but also pathologic pain. In the present study, bupropion-induced antihyperalgesia was dose-dependently reversed by sulpiride, a D2 receptor antagonist. Furthermore, in the microdialysis studies, dopamine levels were increased in the dorsal horn of the spinal cord after bupropion injection. These results indicate that increased dopamine levels and subsequent activation of D2 receptors in the spinal cord strongly contribute to the antihyperalgesic effect of bupropion.

The change over time of the noradrenaline and dopamine contents in the homogenized tissue from the ipsilateral dorsal lumbar spinal cord after SNL was intriguing. A previous study demonstrated plastic changes in descending noradrenergic neurons after nerve injury,12 where the density of the descending noradrenergic fibers and noradrenaline content in the ipsilateral lumbar spinal cord were increased 10 days after SNL in rats. In contrast, Hughes et al.13 reported a loss of noradrenergic fibers in the ipsilateral lumbar spinal cord 19 to 21 days after tibial nerve transection in rats. Although the animal models were different, these results suggest that the tone of the descending noradrenergic system dynamically changes over time after nerve injury. Consistent with these findings, the noradrenaline content in the spinal cord in the present study was increased 2 weeks after SNL, followed by a subsequent decrease to preinjury levels at 3 to 4 weeks. The dopamine content in the ipsilateral lumbar spinal cord was also increased 2 weeks after SNL but then returned to a level similar to that in normal rats. No previous study has examined the plasticity of the descending dopaminergic system after injury; however, our data indicate that the changes in the descending noradrenaline and dopamine systems over time after nerve injury are similar. Several clinically approved treatments for neuropathic pain, including gabapentin34 and antidepressants,3 modulate or mimic the activation of descending noradrenergic pathways to produce analgesia and may overcome or compensate for decreased function of descending inhibitory pathways. We performed behavioral experiments at approximately 3 weeks after SNL surgery. Although we did not compare the efficacy of bupropion across various time points after nerve injury, the plasticity of descending inhibitory systems over time may contribute to the efficacy of antidepressants for neuropathic pain.

Antidepressants, particularly tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors, are widely used for the management of neuropathic pain,2 and it is well known that their analgesic effects are mediated by recruitment of descending inhibitory pathways, such as noradrenergic and serotonergic systems.35 Compared with the large amount of literature on the noradrenergic and serotonergic descending inhibitory systems, however, little information is available regarding the analgesic effects of dopamine. It has been reported that mechanical allodynia is attenuated by systemic administration of bupropion in animal models of neuropathic pain.36,37 In a small trial of 41 human patients with neuropathic pain of different etiologies, bupropion showed strong efficacy for pain reduction,10 and the number needed to treat was calculated as 1.6.11

Taken together with these previous studies, the present findings provide strong evidence of the therapeutic effect of bupropion, a noradrenaline and dopamine reuptake inhibitor, against neuropathic pain symptoms. Bupropion may thus be useful for the treatment of neuropathic pain through a spinal mechanism.

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DISCLOSURES

Name: Hajime Hoshino, MD.

Contribution: This author helped conduct the study, collect data, analyze the data, and prepare the manuscript.

Attestation: Hajime Hoshino approved the final manuscript and reviewed the original study data and data analysis. This author attests to the integrity of the original data and the analysis.

Name: Hideaki Obata, MD, PhD.

Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.

Attestation: Hideaki Obata approved the final manuscript and reviewed the original study data and data analysis. This author attests to the integrity of the original data and the analysis.

Name: Kunie Nakajima, MD, PhD.

Contribution: This author helped design the study and prepare the manuscript.

Attestation: Kunie Nakajima approved the final manuscript and attests to the integrity of the original data and the analysis.

Name: Rie Mieda, MD.

Contribution: This author helped to analyze the data and prepare the manuscript.

Attestation: Rie Mieda approved the final manuscript and attests to the integrity of the original data and the analysis.

Name: Shigeru Saito, MD, PhD.

Contribution: This author helped to design the study, analyze the data, and prepare the manuscript.

Attestation: Shigeru Saito approved the final manuscript, attests to the integrity of the original data and the analysis, and is the archival author.

This manuscript was handled by: Jianren Mao, MD, PhD.

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