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The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn
Neuroscience Letters 583 (2014) 103–107
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn Hyung Gon Lee a , Jeong Il Choi a , Myung Ha Yoon a , Hideaki Obata b , Shigeru Saito b , Woong Mo Kim a,c,∗ a Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501-757, Republic of Korea b Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showa, Maebashi, Gunma 371-8511, Japan c Research Institute of Medical Sciences, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501-757, Republic of Korea
h i g h l i g h t s • Intrathecal tianeptine reduced mechanical allodynia by spinal nerve ligation. • The tianeptine effect was reversed by serotonergic and adrenergic receptor antagonists. • Microdialysis revealed increases in spinal serotonin and norepinephrine by tianeptine.
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Article history: Received 18 March 2014 Received in revised form 25 July 2014 Accepted 6 September 2014 Available online 16 September 2014 Keywords: Tianeptine Intrathecal Antinociception Microdialysis Serotonin Norepinephrine
a b s t r a c t The purpose of this study was to validate the effects of tianeptine on serotonergic and noradrenergic neurotransmission in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague–Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of intrathecally administered tianeptine on mechanical allodynia were assessed. Dihydroergocristine or yohimbine, a serotonergic or ␣-2 adrenergic receptor antagonists, respectively, were intrathecally administered 10 min before tianeptine to investigate its mechanism of action. Additionally microdialysis studies were performed to measure the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the spinal dorsal horn following tianeptine administration. Intrathecal tianeptine significantly increased the paw withdrawal thresholds in a dose-dependent manner and the antiallodynic effect was antagonized by dihydroergocristine and yohimbine. Microdialysis studies revealed that tianeptine increased the levels of 5-HT and NE in the spinal dorsal horn. These findings suggest that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) is an atypical antidepressant that exhibits structural similarities to tricyclic antidepressants (TCAs) but with distinct neurochemical properties. Typical antidepressants affect the presynaptic reuptake of serotonin (5-hydroxytriptamine,
∗ Corresponding author at: Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501757, Republic of Korea. Tel.: +82 62 220 6895; fax: +82 62 232 6294. E-mail address: [email protected] (W.M. Kim). http://dx.doi.org/10.1016/j.neulet.2014.09.022 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
5-HT) and norepinephrine (NE), increasing their levels in the synaptic cleft [1]. However, tianeptine reportedly either has the opposite effect on extracellular levels of 5-HT or NE [2,3] or does not elicit any marked alterations [4,5]. Nevertheless, its antidepressant efficacy has been clearly demonstrated in patients with depression [6,7], and its antinociceptive activity has been reported in animal models of acute nociception [8], morphine tolerance [9], and inflammatory pain [10]. In a study by Uzbay et al. [8], the antinociceptive activity of tianeptine was thought to be associated with increased serotonergic activity because its effects were blocked by parachlorophenylalanine. Parachlorophenylalanine is a competitive inhibitor of 5-hydroxy-tryptophan hydroxylase, which is involved in 5-HT synthesis. In our previous report [10], intrathecally administered tianeptine reduced the flinching
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response evoked by formalin injection, and pretreatment with 5-HT, ␣-1, and ␣-2 adrenergic receptor antagonists attenuated the effect of tianeptine. Therefore, we assumed that the serotonergic and adrenergic systems may, at least in part, mediate the spinal antinociception of tianeptine. However, we could not formulate a definitive conclusion based on our results, because our observations were contradictory to those of other studies. The aim of this study was to validate the effects of tianeptine on serotonergic and adrenergic neurotransmission in a rat model of neuropathic pain. First, we examined the effects of intrathecally administered tianeptine on mechanical allodynia in spinal nerveligated rats and the effects of pretreatment with pharmacological antagonists of 5-HT and NE receptors on tianeptine analgesia. To further investigate the effects of tianeptine on these neurotransmitters, we measured the extracellular levels of 5-HT and NE in the spinal dorsal horn by microdialysis.
2. Materials and methods The study was approved by The Institutional Animal Care and Use Committee of Chonnam National University and Gunma University Graduate School of Medicine. The microdialysis study was performed at Gunma University, and all other experiments were performed at Chonnam National University. Male Sprague–Dawley rats weighing 250–300 g were used in the experiments. The rats were housed under an alternating 12-h light/dark cycle in individual cages in a temperature-controlled room (22 ◦ C ± 0.5 ◦ C) with free access to food and water. Neuropathic pain was evoked by L5 and L6 spinal nerve ligation (SNL) according to the method described by Kim and Chung [11]. Rats exhibiting an inability to flex the left hind limb, indicating L4 nerve damage, were excluded from the study. Animals displaying a 50% withdrawal threshold of ≤ 4.0 g by postoperative day 5 were considered to be neuropathic and were intrathecally catheterized with polyethylene-10 tubing for drug administration, using a method described by Yaksh and Rudy [12]. Rats exhibiting any motor or sensory deficits were euthanized immediately with an overdose of sevoflurane. All rats were allowed to recover for at least 5 days postsurgically. The following drugs were used in this study: tianeptine (JEIL Pharm. Co., Ltd., Seoul, Korea), dihydroergocristine mesylate (Research Biochemical Internationals, Natick, MA, USA), and yohimbine hydrochloride (Sigma–Aldrich Co., St. Louis, MO, USA). The tianeptine was dissolved in 0.9% saline, and the others were dissolved in dimethylsulfoxide (DMSO). Intrathecal administration of these drugs was performed using a hand-driven, gear-operated syringe pump. All drugs were administered as 10-L volumes of solution followed by an additional 10 L of 0.9% saline to flush the catheter. Behavioral testing was performed by an investigator blinded to the experimental drug and dose. To determine the mechanical withdrawal threshold, eight von Frey filaments (Stoelting, Wood Dale, IL, USA) with logarithmically increasing stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, and 15.0 g) were applied perpendicularly to the plantar surface of the rat’s paw using an up–down method. A force just sufficient to bend the filament was applied for 5 s, and a positive response was assumed when abrupt withdrawal or licking responses were exhibited. The 50% withdrawal threshold was then calculated by a method described previously [13]. Five to seven days after intrathecal catheterization, the rats were randomly allocated into experimental groups for intrathecal administration of either an experimental drug or vehicle solution. To assess the efficacy of tianeptine, increasing doses of tianeptine (30, 100, 300, and 1,000 g in 10 L, n = 6) were administered intrathecally. The route and doses of tianeptine were
determined based on the previous study [10]. The withdrawal threshold measured prior to SNL was regarded as the preligation baseline threshold. The withdrawal threshold determined just before intrathecal drug delivery was regarded as the postligation control value. After administration of the experimental drugs, the withdrawal threshold was determined at 15, 30, 60, 90, 120, 150, and 180 min. To determine whether the effect of intrathecal tianeptine is mediated via serotonergic and/or adrenergic transmission, dihydroergocristine (serotonin receptor antagonist, 3 g) and yohimbine (␣-2 adrenergic receptor antagonist, 10 g) were injected intrathecally 10 min prior to the administration of tianeptine. The doses of dihydroergocristine and yohimbine were chosen based on a previous study in which the maximal doses that did not affect the formalin response (control response) were determined [14]. Microdialysis studies were performed 10–14 days after SNL as described previously [15]. The rats were anesthetized with isoflurane in 100% oxygen, and the right femoral vein was cannulated for infusion at a rate of 1 ml/h. The rectal temperature was maintained at 37–38 ◦ C with a heating pad placed under the animal. After creation of a thoracolumbar laminectomy, the L3-to-L5 segment of the spinal cord was exposed, and the surface of the dura was covered with mineral oil. The rat was then placed in a stereotaxic holder. After opening the dura, a microdialysis probe (OD, 0.22 mm; ID, 0.20 mm; length, 1 mm; Eicom Co., Kyoto, Japan) was advanced at an angle of 30◦ and to a depth of 1 mm using a micromanipulator (model MM-3; Narishige, Tokyo, Japan), such that it could be inserted into the superficial layer of the dorsal horn. The microdialysis probe was perfused with Ringer’s solution (147.0 mmol/L NaCl, 4.0 mmol/L KCl, and 2.3 mmol/L CaCl2 ) at a constant flow rate (1 L/min) using a microsyringe pump (ESP-64; Eicom Co., Kyoto, Japan). After 120 min of constant perfusion, two consecutive samples were collected to determine the basal 5-HT and NE concentrations in the dialysate, and either saline or tianeptine (1000 g) was delivered through an intrathecal catheter. Thereafter, the 15-min perfusate fractions were collected into an autoinjector (EAS-20; Eicom Co.). The samples (15 l) were automatically injected into the HTEC-500 system (Eicom Co.) to analyze the 5-HT and NE concentrations using high-performance liquid chromatography (HPLC) with electrochemical detection. The chromatographic conditions were as follows. The mobile phase comprised 0.1 mol/L ammonium acetate buffer, pH 6.0, methanol (7:3 vol/vol) containing 0.05 mol/L sodium sulfonate, and 50 mg/L EDTA-2Na. The column was an EICOMPAC CAX (2.0 × 200.0 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 at 0.45 V. The detector temperature was set at 35.0 ◦ C. The retention time for NE was 5.4 min, and that for 5-HT was 13.1 min. The detection limit of this assay was 30 fg per injection (information from Eicom Co.). Data are shown as means ± SEM. The time–response data are presented as the mechanical withdrawal threshold in grams. The dose–response data are presented as the area under the time course curves for each dose using the trapezoidal rule and were analyzed using one-way analysis of variance (ANOVA) with Bonferroni adjustment for post hoc analysis. The antagonistic effects of tianeptine were compared using an unpaired t test. To calculate the half-maximal effective dose (ED50 ) and its 95% confidence interval (CI) [16], the withdrawal threshold data from von Frey filament testing were converted to percentages of maximum possible effect (%MPE) according to the following formula: %MPE = ([postdrug threshold − postligation control threshold]/[cutoff threshold − postligation control threshold]) × 100. Microdialysis data were analyzed using repeatedmeasures ANOVA. Differences were considered statistically significant at a P value < 0.05.
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Fig. 1. Effects of intrathecal tianeptine on the hind paw withdrawal response after spinal nerve ligation. Data are presented as the withdrawal threshold (g). Each line represents the means ± SEM of 6 rats. Baseline (BL) and control data were measured prior to nerve ligation and immediately before intrathecal delivery of drugs, respectively. * P < 0.05 compared to control data.
3. Results SNL resulted in a significant lowering of the paw withdrawal thresholds at the injured site. This characteristic mechanical allodynia appeared after SNL and persisted for more than 21 days, as observed in a previous study [17]. The baseline threshold after SNL did not differ among the groups. While intrathecal DMSO or saline had no effect, intrathecal tianeptine significantly increased the paw withdrawal thresholds (4.16% ± 2.66% vs. 100% of MPE, respectively) in a dose-dependent manner, and its peak effect was observed at 15–30 min after injection and lasted up to 90 min (Figs. 1, 2). The ED50 value of tianeptine was 102.1 g (95% CI, 85.4–122.0 g). The antiallodynic effect of intrathecal tianeptine was antagonized by yohimbine and dihydroergocristine (Fig. 2), as observed in our previous study using a formalin model. The baseline 5-HT concentration before drug injection in the saline and tianeptine groups after SNL was 20.69 ± 4.43 ng/L and 25.48 ± 1.82 ng/L, respectively, and the difference between the two groups was not statistically significant. The baseline levels of
Fig. 3. Microdialysis measuring spinal 5-HT (A) and NE (B) levels. Spinal nerveligated rats (n = 6) received intrathecal saline or tianeptine (1000 g). Data are presented over time as a percentage of the baseline. * P < 0.05 compared to baseline (BL) value. † P < 0.05 compared with saline-treated group.
NE were also similar between the two groups (23.69 ± 10.29 ng/L in the saline group and 16.77 ± 8.35 ng/L in the tianeptine group). The extracellular concentrations of 5-HT and NE in the spinal dorsal horn were significantly higher after tianeptine administration than before administration. In rats that underwent intrathecal administration of 1,000 g tianeptine, the 5-HT concentrations increased within 15 min after injection, peaked at 30 min to approximately 15-fold the baseline value, and gradually decreased within 2 h after drug administration (Fig. 3A). Intrathecal delivery of tianeptine also increased the level of NE in the dialysate within 15 min after injection, reaching more than twice the baseline value at 30 min, and gradually decreased within 1.5 h (Fig. 3B). In the saline-treated group, the 5-HT and NE concentrations in the dialysates after injection did not change over time (Fig. 3A and B). 4. Discussion
Fig. 2. Dose-response data of intrathecal tianeptine on mechanical withdrawal threshold and the effects of dihydroergocristine and yohimbine on tianeptineinduced analgesia. Data are presented as the area under the time course curves for the mechanical withdrawal threshold. Each bar represents the means ± SEM of 6 rats. Dihydroergocristine and yohimbine were given 10 min before tianeptine administration. * P < 0.05 compared with saline group. † P < 0.05 compared with tianeptine 30 g group, ‡ P < 0.05 compared with tianeptine 100 g group, § P < 0.05 compared with tianeptine only (1,000 g) group.
In this study, intrathecally administered tianeptine reduced mechanical allodynia induced by SNL in a dose-dependent manner. As observed in a previous study of an inflammatory pain model [10], the effect of tianeptine was attenuated by pretreatment with 5-HT and adrenergic receptor antagonists. Furthermore, direct measurement of 5-HT and NE in the spinal dorsal horn by microdialysis clarified that tianeptine increased the level of 5-HT and NE in the extracellular space. These observations clearly indicate that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level.
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Neuropathic pain arises from damage to the peripheral or central nervous system [18]. Despite intensive investigation, the detailed mechanisms underlying neuropathic pain remain unclear. Consequently, the current therapeutic approaches to relieve neuropathic pain are limited, and continued use of some medications can lead to a variety of adverse events. Therefore, further studies for developing safer and more effective pain therapeutics are required. In this regard, tianeptine may serve as an alternative approach to the management of neuropathic pain. The analgesic efficacy of tianeptine was elucidated by several studies, including our own [8–10]. Compared with TCAs or selective serotonin-reuptake inhibitors, tianeptine reportedly exhibits a lower probability of undesirable side effects on sedative, cardiovascular, and cognitive functions and a lower possibility of sexual dysfunction or nausea. Tianeptine has been termed an atypical antidepressant, because its neurobiological properties are reportedly opposite those of other antidepressants, thus challenging the monoaminergic hypothesis of depression and mechanisms of action of most known antidepressants [7]. Nevertheless, the present study has clearly demonstrated that intrathecally administered tianeptine increases the extracellular level of 5-HT and NE in the spinal cord. These findings, which markedly contrasted those of the previous report, may be explained by several factors, including differences in experimental techniques and routes of tianeptine administration. Earlier studies reported that tianeptine decreased the extracellular level of 5-HT and hypothesized that this phenomenon might be mediated by enhanced neuronal uptake of 5-HT [2,19]. However, this finding was obtained from ex vivo studies of cortical and hippocampal synaptosomes, and its validity has been contested in terms of technical limitations [4]. In studies utilizing previous techniques of in vivo microdialysis, tianeptine inhibited the increase in extracellular 5-HT in the frontal cortex following administration of 5-hydroxytryptophan [20] and attenuated the K+ -evoked increase in extracellular 5-HT in the hippocampus [21]. Because of the detection limit of monoamine in the dialysate by HPLC at that time, these studies were performed using stimulus-evoked release of 5-HT to artificially raise its concentration to a detectable level. Consequently, this technique also has some limitations, because the excess endogenous 5-HT resulting from stimulation (e.g., by 5-hydroxytryptophan or K+ ) might have activated autoreceptors, leading to a decrease in 5-HT release at nerve endings [22], thus possibly affecting the tianeptine-induced change. In a more recent investigation, the extracellular concentrations of 5-HT measured in the frontal cortex and the raphe nuclei of freely moving rats were not altered markedly after tianeptine administration [4]. However, the dose of tianeptine used in these experiments should be noted. According to the commonly used equianalgesic conversion rules [23], the systemically administered tianeptine at a dose of 10 mg/kg in the above-mentioned study may be equal to 25–30 g of intrathecal tianeptine for rats weighing 250–300 g in the current study. As shown in Fig. 2, an analgesic effect was not exhibited with ≤30 g tianeptine. Therefore, we assume that the findings of this previous microdialysis study may have resulted from an insufficient dose of tianeptine compared with the current investigation. Although the present study is the first to demonstrate the analgesic efficacy of intrathecally delivered tianeptine in a neuropathic pain model and to elucidate its mechanism in terms of serotonergic and adrenergic transmission in the spinal cord, there are some limitations. First, we could not clarify the mechanism of the increased extracellular concentrations of 5-HT and NE following tianeptine administration. One possible speculation regarding this mechanism is that tianeptine enhances 5-HT reuptake and facilitates 5-HT turnover and release [24]. Increased 5-HT may in turn induce subsequent release of NE [25]. The in vivo microdialysis study might have detected this increase. Next, as shown in the previous study, serotonergic and adrenergic antagonists only
partially blocked the analgesic effect of tianeptine [10]. Therefore, it is important to consider other mechanisms beyond the monoaminergic neurotransmission that may underlie tianeptineelicited analgesia. For example, acetylcholine, which may serve as a target for the antidepressant action of tianeptine [26], can produce antinociception via nicotinic receptors on primary afferent fibers [27]. Additionally, the activation of nicotinic receptors localized on the terminals of the serotonergic and adrenergic pathways may enhance the release of 5-HT and NE, respectively [28,29]. Moreover, glutamate is reportedly involved in both the antidepressant action of tianeptine and the induction of antinociception [7,30]. Therefore, the roles of these neurotransmitters in tianeptine analgesia remain to be elucidated in further studies. Finally, tianeptine is not currently available for neuraxial delivery. However, in the future, neuraxial administration of tianeptine may be considered an effective alternative strategy for management of neuropathic pain. In conclusion, intrathecally delivered tianeptine reversed mechanical allodynia in spinal nerve-ligated rats. The antinociceptive effect of tianeptine may be mediated by increased levels of 5-HT and NE in the spinal cord. Tianeptine may be used effectively in the future to treat neuropathic pain by intrathecal or epidural administration.
Acknowledgements This work was supported by a research grant from the Research Institute of Medical Sciences, Chonnam National University (2011CURIMS-DR001) and grant from the Ministry of Science, ICT and Future Planning, and National Research Foundation of Korea (NRF2012R1A1A1004608).
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
The antiallodynic effect of intrathecal tianeptine is exerted by increased serotonin and norepinephrine in the spinal dorsal horn Hyung Gon Lee a , Jeong Il Choi a , Myung Ha Yoon a , Hideaki Obata b , Shigeru Saito b , Woong Mo Kim a,c,∗ a Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501-757, Republic of Korea b Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showa, Maebashi, Gunma 371-8511, Japan c Research Institute of Medical Sciences, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501-757, Republic of Korea
h i g h l i g h t s • Intrathecal tianeptine reduced mechanical allodynia by spinal nerve ligation. • The tianeptine effect was reversed by serotonergic and adrenergic receptor antagonists. • Microdialysis revealed increases in spinal serotonin and norepinephrine by tianeptine.
a r t i c l e
i n f o
Article history: Received 18 March 2014 Received in revised form 25 July 2014 Accepted 6 September 2014 Available online 16 September 2014 Keywords: Tianeptine Intrathecal Antinociception Microdialysis Serotonin Norepinephrine
a b s t r a c t The purpose of this study was to validate the effects of tianeptine on serotonergic and noradrenergic neurotransmission in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague–Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of intrathecally administered tianeptine on mechanical allodynia were assessed. Dihydroergocristine or yohimbine, a serotonergic or ␣-2 adrenergic receptor antagonists, respectively, were intrathecally administered 10 min before tianeptine to investigate its mechanism of action. Additionally microdialysis studies were performed to measure the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the spinal dorsal horn following tianeptine administration. Intrathecal tianeptine significantly increased the paw withdrawal thresholds in a dose-dependent manner and the antiallodynic effect was antagonized by dihydroergocristine and yohimbine. Microdialysis studies revealed that tianeptine increased the levels of 5-HT and NE in the spinal dorsal horn. These findings suggest that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) is an atypical antidepressant that exhibits structural similarities to tricyclic antidepressants (TCAs) but with distinct neurochemical properties. Typical antidepressants affect the presynaptic reuptake of serotonin (5-hydroxytriptamine,
∗ Corresponding author at: Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, 42 Jebongro, Donggu, Gwangju 501757, Republic of Korea. Tel.: +82 62 220 6895; fax: +82 62 232 6294. E-mail address: [email protected] (W.M. Kim). http://dx.doi.org/10.1016/j.neulet.2014.09.022 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
5-HT) and norepinephrine (NE), increasing their levels in the synaptic cleft [1]. However, tianeptine reportedly either has the opposite effect on extracellular levels of 5-HT or NE [2,3] or does not elicit any marked alterations [4,5]. Nevertheless, its antidepressant efficacy has been clearly demonstrated in patients with depression [6,7], and its antinociceptive activity has been reported in animal models of acute nociception [8], morphine tolerance [9], and inflammatory pain [10]. In a study by Uzbay et al. [8], the antinociceptive activity of tianeptine was thought to be associated with increased serotonergic activity because its effects were blocked by parachlorophenylalanine. Parachlorophenylalanine is a competitive inhibitor of 5-hydroxy-tryptophan hydroxylase, which is involved in 5-HT synthesis. In our previous report [10], intrathecally administered tianeptine reduced the flinching
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response evoked by formalin injection, and pretreatment with 5-HT, ␣-1, and ␣-2 adrenergic receptor antagonists attenuated the effect of tianeptine. Therefore, we assumed that the serotonergic and adrenergic systems may, at least in part, mediate the spinal antinociception of tianeptine. However, we could not formulate a definitive conclusion based on our results, because our observations were contradictory to those of other studies. The aim of this study was to validate the effects of tianeptine on serotonergic and adrenergic neurotransmission in a rat model of neuropathic pain. First, we examined the effects of intrathecally administered tianeptine on mechanical allodynia in spinal nerveligated rats and the effects of pretreatment with pharmacological antagonists of 5-HT and NE receptors on tianeptine analgesia. To further investigate the effects of tianeptine on these neurotransmitters, we measured the extracellular levels of 5-HT and NE in the spinal dorsal horn by microdialysis.
2. Materials and methods The study was approved by The Institutional Animal Care and Use Committee of Chonnam National University and Gunma University Graduate School of Medicine. The microdialysis study was performed at Gunma University, and all other experiments were performed at Chonnam National University. Male Sprague–Dawley rats weighing 250–300 g were used in the experiments. The rats were housed under an alternating 12-h light/dark cycle in individual cages in a temperature-controlled room (22 ◦ C ± 0.5 ◦ C) with free access to food and water. Neuropathic pain was evoked by L5 and L6 spinal nerve ligation (SNL) according to the method described by Kim and Chung [11]. Rats exhibiting an inability to flex the left hind limb, indicating L4 nerve damage, were excluded from the study. Animals displaying a 50% withdrawal threshold of ≤ 4.0 g by postoperative day 5 were considered to be neuropathic and were intrathecally catheterized with polyethylene-10 tubing for drug administration, using a method described by Yaksh and Rudy [12]. Rats exhibiting any motor or sensory deficits were euthanized immediately with an overdose of sevoflurane. All rats were allowed to recover for at least 5 days postsurgically. The following drugs were used in this study: tianeptine (JEIL Pharm. Co., Ltd., Seoul, Korea), dihydroergocristine mesylate (Research Biochemical Internationals, Natick, MA, USA), and yohimbine hydrochloride (Sigma–Aldrich Co., St. Louis, MO, USA). The tianeptine was dissolved in 0.9% saline, and the others were dissolved in dimethylsulfoxide (DMSO). Intrathecal administration of these drugs was performed using a hand-driven, gear-operated syringe pump. All drugs were administered as 10-L volumes of solution followed by an additional 10 L of 0.9% saline to flush the catheter. Behavioral testing was performed by an investigator blinded to the experimental drug and dose. To determine the mechanical withdrawal threshold, eight von Frey filaments (Stoelting, Wood Dale, IL, USA) with logarithmically increasing stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, and 15.0 g) were applied perpendicularly to the plantar surface of the rat’s paw using an up–down method. A force just sufficient to bend the filament was applied for 5 s, and a positive response was assumed when abrupt withdrawal or licking responses were exhibited. The 50% withdrawal threshold was then calculated by a method described previously [13]. Five to seven days after intrathecal catheterization, the rats were randomly allocated into experimental groups for intrathecal administration of either an experimental drug or vehicle solution. To assess the efficacy of tianeptine, increasing doses of tianeptine (30, 100, 300, and 1,000 g in 10 L, n = 6) were administered intrathecally. The route and doses of tianeptine were
determined based on the previous study [10]. The withdrawal threshold measured prior to SNL was regarded as the preligation baseline threshold. The withdrawal threshold determined just before intrathecal drug delivery was regarded as the postligation control value. After administration of the experimental drugs, the withdrawal threshold was determined at 15, 30, 60, 90, 120, 150, and 180 min. To determine whether the effect of intrathecal tianeptine is mediated via serotonergic and/or adrenergic transmission, dihydroergocristine (serotonin receptor antagonist, 3 g) and yohimbine (␣-2 adrenergic receptor antagonist, 10 g) were injected intrathecally 10 min prior to the administration of tianeptine. The doses of dihydroergocristine and yohimbine were chosen based on a previous study in which the maximal doses that did not affect the formalin response (control response) were determined [14]. Microdialysis studies were performed 10–14 days after SNL as described previously [15]. The rats were anesthetized with isoflurane in 100% oxygen, and the right femoral vein was cannulated for infusion at a rate of 1 ml/h. The rectal temperature was maintained at 37–38 ◦ C with a heating pad placed under the animal. After creation of a thoracolumbar laminectomy, the L3-to-L5 segment of the spinal cord was exposed, and the surface of the dura was covered with mineral oil. The rat was then placed in a stereotaxic holder. After opening the dura, a microdialysis probe (OD, 0.22 mm; ID, 0.20 mm; length, 1 mm; Eicom Co., Kyoto, Japan) was advanced at an angle of 30◦ and to a depth of 1 mm using a micromanipulator (model MM-3; Narishige, Tokyo, Japan), such that it could be inserted into the superficial layer of the dorsal horn. The microdialysis probe was perfused with Ringer’s solution (147.0 mmol/L NaCl, 4.0 mmol/L KCl, and 2.3 mmol/L CaCl2 ) at a constant flow rate (1 L/min) using a microsyringe pump (ESP-64; Eicom Co., Kyoto, Japan). After 120 min of constant perfusion, two consecutive samples were collected to determine the basal 5-HT and NE concentrations in the dialysate, and either saline or tianeptine (1000 g) was delivered through an intrathecal catheter. Thereafter, the 15-min perfusate fractions were collected into an autoinjector (EAS-20; Eicom Co.). The samples (15 l) were automatically injected into the HTEC-500 system (Eicom Co.) to analyze the 5-HT and NE concentrations using high-performance liquid chromatography (HPLC) with electrochemical detection. The chromatographic conditions were as follows. The mobile phase comprised 0.1 mol/L ammonium acetate buffer, pH 6.0, methanol (7:3 vol/vol) containing 0.05 mol/L sodium sulfonate, and 50 mg/L EDTA-2Na. The column was an EICOMPAC CAX (2.0 × 200.0 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 at 0.45 V. The detector temperature was set at 35.0 ◦ C. The retention time for NE was 5.4 min, and that for 5-HT was 13.1 min. The detection limit of this assay was 30 fg per injection (information from Eicom Co.). Data are shown as means ± SEM. The time–response data are presented as the mechanical withdrawal threshold in grams. The dose–response data are presented as the area under the time course curves for each dose using the trapezoidal rule and were analyzed using one-way analysis of variance (ANOVA) with Bonferroni adjustment for post hoc analysis. The antagonistic effects of tianeptine were compared using an unpaired t test. To calculate the half-maximal effective dose (ED50 ) and its 95% confidence interval (CI) [16], the withdrawal threshold data from von Frey filament testing were converted to percentages of maximum possible effect (%MPE) according to the following formula: %MPE = ([postdrug threshold − postligation control threshold]/[cutoff threshold − postligation control threshold]) × 100. Microdialysis data were analyzed using repeatedmeasures ANOVA. Differences were considered statistically significant at a P value < 0.05.
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Fig. 1. Effects of intrathecal tianeptine on the hind paw withdrawal response after spinal nerve ligation. Data are presented as the withdrawal threshold (g). Each line represents the means ± SEM of 6 rats. Baseline (BL) and control data were measured prior to nerve ligation and immediately before intrathecal delivery of drugs, respectively. * P < 0.05 compared to control data.
3. Results SNL resulted in a significant lowering of the paw withdrawal thresholds at the injured site. This characteristic mechanical allodynia appeared after SNL and persisted for more than 21 days, as observed in a previous study [17]. The baseline threshold after SNL did not differ among the groups. While intrathecal DMSO or saline had no effect, intrathecal tianeptine significantly increased the paw withdrawal thresholds (4.16% ± 2.66% vs. 100% of MPE, respectively) in a dose-dependent manner, and its peak effect was observed at 15–30 min after injection and lasted up to 90 min (Figs. 1, 2). The ED50 value of tianeptine was 102.1 g (95% CI, 85.4–122.0 g). The antiallodynic effect of intrathecal tianeptine was antagonized by yohimbine and dihydroergocristine (Fig. 2), as observed in our previous study using a formalin model. The baseline 5-HT concentration before drug injection in the saline and tianeptine groups after SNL was 20.69 ± 4.43 ng/L and 25.48 ± 1.82 ng/L, respectively, and the difference between the two groups was not statistically significant. The baseline levels of
Fig. 3. Microdialysis measuring spinal 5-HT (A) and NE (B) levels. Spinal nerveligated rats (n = 6) received intrathecal saline or tianeptine (1000 g). Data are presented over time as a percentage of the baseline. * P < 0.05 compared to baseline (BL) value. † P < 0.05 compared with saline-treated group.
NE were also similar between the two groups (23.69 ± 10.29 ng/L in the saline group and 16.77 ± 8.35 ng/L in the tianeptine group). The extracellular concentrations of 5-HT and NE in the spinal dorsal horn were significantly higher after tianeptine administration than before administration. In rats that underwent intrathecal administration of 1,000 g tianeptine, the 5-HT concentrations increased within 15 min after injection, peaked at 30 min to approximately 15-fold the baseline value, and gradually decreased within 2 h after drug administration (Fig. 3A). Intrathecal delivery of tianeptine also increased the level of NE in the dialysate within 15 min after injection, reaching more than twice the baseline value at 30 min, and gradually decreased within 1.5 h (Fig. 3B). In the saline-treated group, the 5-HT and NE concentrations in the dialysates after injection did not change over time (Fig. 3A and B). 4. Discussion
Fig. 2. Dose-response data of intrathecal tianeptine on mechanical withdrawal threshold and the effects of dihydroergocristine and yohimbine on tianeptineinduced analgesia. Data are presented as the area under the time course curves for the mechanical withdrawal threshold. Each bar represents the means ± SEM of 6 rats. Dihydroergocristine and yohimbine were given 10 min before tianeptine administration. * P < 0.05 compared with saline group. † P < 0.05 compared with tianeptine 30 g group, ‡ P < 0.05 compared with tianeptine 100 g group, § P < 0.05 compared with tianeptine only (1,000 g) group.
In this study, intrathecally administered tianeptine reduced mechanical allodynia induced by SNL in a dose-dependent manner. As observed in a previous study of an inflammatory pain model [10], the effect of tianeptine was attenuated by pretreatment with 5-HT and adrenergic receptor antagonists. Furthermore, direct measurement of 5-HT and NE in the spinal dorsal horn by microdialysis clarified that tianeptine increased the level of 5-HT and NE in the extracellular space. These observations clearly indicate that tianeptine may be effective for the management of neuropathic pain and that its analgesic mechanism is exerted by increased levels of 5-HT and NE in the synaptic cleft at the spinal level.
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Neuropathic pain arises from damage to the peripheral or central nervous system [18]. Despite intensive investigation, the detailed mechanisms underlying neuropathic pain remain unclear. Consequently, the current therapeutic approaches to relieve neuropathic pain are limited, and continued use of some medications can lead to a variety of adverse events. Therefore, further studies for developing safer and more effective pain therapeutics are required. In this regard, tianeptine may serve as an alternative approach to the management of neuropathic pain. The analgesic efficacy of tianeptine was elucidated by several studies, including our own [8–10]. Compared with TCAs or selective serotonin-reuptake inhibitors, tianeptine reportedly exhibits a lower probability of undesirable side effects on sedative, cardiovascular, and cognitive functions and a lower possibility of sexual dysfunction or nausea. Tianeptine has been termed an atypical antidepressant, because its neurobiological properties are reportedly opposite those of other antidepressants, thus challenging the monoaminergic hypothesis of depression and mechanisms of action of most known antidepressants [7]. Nevertheless, the present study has clearly demonstrated that intrathecally administered tianeptine increases the extracellular level of 5-HT and NE in the spinal cord. These findings, which markedly contrasted those of the previous report, may be explained by several factors, including differences in experimental techniques and routes of tianeptine administration. Earlier studies reported that tianeptine decreased the extracellular level of 5-HT and hypothesized that this phenomenon might be mediated by enhanced neuronal uptake of 5-HT [2,19]. However, this finding was obtained from ex vivo studies of cortical and hippocampal synaptosomes, and its validity has been contested in terms of technical limitations [4]. In studies utilizing previous techniques of in vivo microdialysis, tianeptine inhibited the increase in extracellular 5-HT in the frontal cortex following administration of 5-hydroxytryptophan [20] and attenuated the K+ -evoked increase in extracellular 5-HT in the hippocampus [21]. Because of the detection limit of monoamine in the dialysate by HPLC at that time, these studies were performed using stimulus-evoked release of 5-HT to artificially raise its concentration to a detectable level. Consequently, this technique also has some limitations, because the excess endogenous 5-HT resulting from stimulation (e.g., by 5-hydroxytryptophan or K+ ) might have activated autoreceptors, leading to a decrease in 5-HT release at nerve endings [22], thus possibly affecting the tianeptine-induced change. In a more recent investigation, the extracellular concentrations of 5-HT measured in the frontal cortex and the raphe nuclei of freely moving rats were not altered markedly after tianeptine administration [4]. However, the dose of tianeptine used in these experiments should be noted. According to the commonly used equianalgesic conversion rules [23], the systemically administered tianeptine at a dose of 10 mg/kg in the above-mentioned study may be equal to 25–30 g of intrathecal tianeptine for rats weighing 250–300 g in the current study. As shown in Fig. 2, an analgesic effect was not exhibited with ≤30 g tianeptine. Therefore, we assume that the findings of this previous microdialysis study may have resulted from an insufficient dose of tianeptine compared with the current investigation. Although the present study is the first to demonstrate the analgesic efficacy of intrathecally delivered tianeptine in a neuropathic pain model and to elucidate its mechanism in terms of serotonergic and adrenergic transmission in the spinal cord, there are some limitations. First, we could not clarify the mechanism of the increased extracellular concentrations of 5-HT and NE following tianeptine administration. One possible speculation regarding this mechanism is that tianeptine enhances 5-HT reuptake and facilitates 5-HT turnover and release [24]. Increased 5-HT may in turn induce subsequent release of NE [25]. The in vivo microdialysis study might have detected this increase. Next, as shown in the previous study, serotonergic and adrenergic antagonists only
partially blocked the analgesic effect of tianeptine [10]. Therefore, it is important to consider other mechanisms beyond the monoaminergic neurotransmission that may underlie tianeptineelicited analgesia. For example, acetylcholine, which may serve as a target for the antidepressant action of tianeptine [26], can produce antinociception via nicotinic receptors on primary afferent fibers [27]. Additionally, the activation of nicotinic receptors localized on the terminals of the serotonergic and adrenergic pathways may enhance the release of 5-HT and NE, respectively [28,29]. Moreover, glutamate is reportedly involved in both the antidepressant action of tianeptine and the induction of antinociception [7,30]. Therefore, the roles of these neurotransmitters in tianeptine analgesia remain to be elucidated in further studies. Finally, tianeptine is not currently available for neuraxial delivery. However, in the future, neuraxial administration of tianeptine may be considered an effective alternative strategy for management of neuropathic pain. In conclusion, intrathecally delivered tianeptine reversed mechanical allodynia in spinal nerve-ligated rats. The antinociceptive effect of tianeptine may be mediated by increased levels of 5-HT and NE in the spinal cord. Tianeptine may be used effectively in the future to treat neuropathic pain by intrathecal or epidural administration.
Acknowledgements This work was supported by a research grant from the Research Institute of Medical Sciences, Chonnam National University (2011CURIMS-DR001) and grant from the Ministry of Science, ICT and Future Planning, and National Research Foundation of Korea (NRF2012R1A1A1004608).
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