Anesthesia & Analgesia:
Analgesia: Research Report
Antiallodynic and Antihyperalgesic Effect of Milnacipran in Mice with Spinal Nerve Ligation
Suzuki, Takahiro MD, PhD; Ueta, Kazuyoshi MD, PhD; Tamagaki, Shinji MD; Mashimo, Takashi MD, PhD
From the Department of Anesthesiology, Osaka University Medical School, Osaka, Japan.
Accepted for publication December 3, 2007.
Address correspondence and reprint requests to Takahiro Suzuki, MD, PhD, Department of Anesthesiology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, Japan 565-0871. Address e-mail to firstname.lastname@example.org.
BACKGROUND: The antidepressant, milnacipran, has been reported to have antinociceptive, antiallodynic, and antihyperalgesic effects. In this study, we examined the mechanisms of the antiallodynic and antihyperalgesic effects of milnacipran in a model of neuropathic pain induced by spinal nerve ligation in mice.
METHODS: The fifth left lumbar nerve of male C57BL6 mice was tightly ligated. Withdrawal threshold to tactile stimulation and withdrawal latency to heat stimulation in the injured or contralateral paw was tested by using von Frey filaments and radiant heat, respectively.
RESULTS: Milnacipran was administered either orally (7.5–120 mg/kg), intrathecally, intracerebroventricularly, or locally (210 ng–21 μg). Both systemic, intrathecal and intracerebroventricular milnacipran increased withdrawal threshold and withdrawal latency in nerve-ligated mice whereas local injection had no effect. Depletion of spinal serotonergic or noradrenergic neurons was achieved by use of the specific neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine, applied intrathecally 3 days before evaluation of the analgesic effect of milnacipran. Spinal serotonergic and noradrenergic denervation attenuated the effect of milnacipran in sham-operated mice. In nerve-ligated mice, however, the effect of milnacipran was lost after noradrenergic denervation but not after serotonergic denervation.
CONCLUSIONS: We concluded that the antiallodynic and antihyperalgesic effects of milnacipran on neuropathic pain induced by spinal nerve ligation are principally mediated through action at supraspinal and spinal sites via activation of the spinal noradrenergic system.
The antidepressant, milnacipran, is thought to exert its therapeutic effects by blocking the reuptake of serotonin (5-HT) and noradrenaline (NA).1 Milnacipran is thus similar to the tricyclic antidepressants (TCAs), which also inhibit the reuptake of both 5-HT and NA.2 A major difference, however, between the actions of milnacipran and the TCAs is that the former compound is devoid of interactions at neurotransmitter receptors3,4 and is thus devoid of the troublesome adverse effects that these interactions cause.5 The analgesic effects of TCAs, such as amitriptyline, have been examined using a variety of animal models of pain6–18 and it has been shown to have antinociceptive and antiallodynic effects when administered systemically,6,10,12,16,19 spinally,10 supraspinally,20 and locally.9,11,19,21 Few reports, however, addressed the most important site of action. Among them, Korzeniewska-Rybicka and Plaznik20 concluded that an antidepressant-induced analgesia mainly depends on the supraspinal effect with minor contribution from the spinal mechanisms. And although the analgesic potency has been suggested to result from the inhibition of monoamine reuptake in the central nervous systems,22–24 other mechanisms have also been suggested. Amitriptyline has been found to block N-methyl-d-aspartate (NMDA) receptors,25 to interact directly with opioids receptors26 and to act as a sodium channel blocker.27
Serotonin-noradrenaline reuptake inhibitors developed as new antidepressants have also been shown to have analgesic properties. Venlafaxine has been reported to be effective in patients with diabetic neuropathy28,29 and patients with neuropathy induced by breast cancer treatment.30 In the rat formalin test, serotonin-noradrenaline reuptake inhibitors, duloxetine and milnacipran, showed antinociceptive effects.12,31,32 Duloxetine significantly attenuated formalin-induced paw-licking behavior by intraperitoneal, intrathecal (i.t.), and intracisternal administration.32 Intraperitoneal milnacipran markedly inhibited the formalin-induced pain behavior.12 Milnacipran has been reported to have antiallodynic and antihyperalgesic effects in rat with spinal nerve ligation (SNL).33,34
In the present study, we tested its analgesic effect in mice with SNL. To examine the site of action of milnacipran-induced analgesia, the effects of milnacipran administered via different routes were compared. In addition, the involvement in descending monoaminergic pain inhibitory systems was investigated after chemical denervation of spinal serotonergic or noradrenergic neurons.
Male C57Bl/6 mice (8–12 wks old; Japan SLC, Hamamatsu, Shizuoka, Japan), weighing 25–33 g at the time of testing, were used. They were housed in groups of eight and maintained under standard laboratory conditions with chow and water available ad libitum. Lighting was on a regular light/dark cycle, with lights on from 06:00 to 20:00. All procedures were performed in accordance with the study protocol approved by the Animal Research Committee of Osaka University Medical School.
Milnacipran was provided by Asahi Kasei Pharma (Tokyo, Japan) and was diluted with physiological saline. Desipramine hydrochloride (Wako Pure Chemical Industries, Osaka, Japan), 6-hydroxydopamine (6-OHDA; Sigma, St. Louis, MO), 5,7-dihydroxytryptamine (5,7-DHT; Fluka Chemie, Buchs, SG, Switzerland) were purchased. Milnacipran was administered orally (p.o.) in a volume of 10 mL/kg. The intracerebroventricular injection (i.c.v.) was into the left lateral ventricle. Injection was performed using a Hamilton microsyringe fitted with a 27-gauge needle in a volume of 3 μL, according to the method of Haley and McCormick.35 The site of injection was 2 mm lateral from the midline on a line drawn through the anterior base of the ears, and 3 mm in depth from the skull surface. Injection (i.t.) was performed free-hand between L5 and L6 lumbar space according to the method of Hylden and Wilcox36 using a 30-gauge needle attached to a Hamilton glass microsyringe in a volume of 3 μL. For local injection into the nerve-injured paw, the injection was performed with a syringe with a 30-gauge needle subcutaneously into the dorsal surface of the left hindpaw in a volume of 5 μL.8,9,19 Behavioral tests were started 60 min after oral administration or 15 min after i.c.v., i.t. and local injection.
The left fifth lumbar nerve was tightly ligated with 6-0 silk under sevoflurane anesthesia as previously described.37 Control animals were sham-operated by exposing, but not ligating the left fifth lumbar nerve.
Behavioral tests were performed at 7 or 10 days after nerve ligation.
To measure mechanical sensitivity of the hind paw, mice were placed in individual plastic boxes on a mesh floor and allowed to acclimatize for 30 min. A series of filaments with logarithmically incremental stiffness from 1.5–15 g (Stoelting, Wood Dale, IL) was applied perpendicularly to the plantar surface of the hind paw with sufficient force to bend the filaments for 6 s. Brisk withdrawal or paw flinching were considered a positive response. In the absence of a response, the filament of the next greater force was applied. In the presence of a response, the filament of the next lower force was applied. The tactile stimulus producing a 50% likelihood of withdrawal was determined using the “up-down” calculating method.38
Thermal sensitivity was assessed by the method of Hargreaves et al.39 A radiant heat beam (Paw Stimulator Analgesia Meter Model 390, IITC) was focused on the left hind limb footpads placed on a glass surface. The withdrawal-response latency (in s) was measured with a 20-s cut-off time.
Open Field Test
Mice were placed in the 60 × 60 cm field surrounded by a 50 cm wall under dim light. Movement was measured for 10 min to assess total distance traveled and the time spent in the center zone (area >12 cm from walls). Total distance traveled was indicative of general activity level, whereas the percent time spent in the center was used as an index of the anxiety state of mice.40
In all cases, the experimenter was blind to the type of operation (sham or ligated) and drugs administered.
Treatment With Neurotoxins and Neurochemical Analysis
The neurotoxins, 6-OHDA and 5,7-DHT, were used according to the method of Nakazawa et al.41 with some modifications42 because these neurotoxins do not pass the blood-brain barrier.41 The details of neurotoxin treatment and neurochemical analysis were described in our previous report.42 Briefly, i.t. injection of 6-OHDA (20 μg in 5 μL per mouse) for selective denervation of spinal noradrenergic terminals, or 5,7-DHT for selective denervation of spinal serotonergic terminals (20 μg in 5 μL per mouse) was performed 3 days before behavioral testing. To block the uptake of 5,7-DHT into noradrenergic terminals, desipramine (25 mg/kg) was administered intraperitoneally 30 min before i.t. injection of 5,7-DHT. Saline (5 μL) was injected i.t. as a control. To determine the contents of NA, 5-HT and dopamine (DA) in the spinal cord, the lumber enlargement (approximately 1 cm) was isolated from normal (nonoperated) mice on the same schedule as the antinociceptive test after treatment with the neurotoxins. Tissue was homogenized with 0.28% perchloric acid including 0.2% EDTA 2Na and 0.002% ascorbic acid, and centrifuged (2000g × 30 min) at 4°C. The supernatant was stored at −80°C until the analysis. The content of monoamines was measured by following high performance liquid chromatography (HPLC) procedures. Catecholamines were measured by diphenylethylenediamine condensation method. Catecholamines in samples were purified through the precolumn. Purified catecholamines were separated by analytical column (Wakosil-II 4.6 × 150 mm) maintained at 20°C. HPLC mobile phase consisted of ammonium nitrate buffer and the flow rate was 0.7 mL/min. Separated catecholamines were converted to diphenylethylenediamine derivatives, and fluorescence intensity was measured in a detector (L-7480, Hitachi) at 483 nm wavelength with an excitation wavelength at 347 nm. 5-HT was measured by naive fluorimetric detection. 5-HT in the sample was purified through the precolumn. HPLC mobile phase was phosphate buffer and the flow rate was 0.7 mL/min. Analytical column (Wakosil-II, 4.6 × 150 mm, Tosoh) maintained at 22°C was monitored by a fluorescence detector (L-7480, Hitachi) at 340 nm wavelength with an excitation wavelength at 280 nm.
Seventy-eight groups consisting of eight mice were enrolled. In the experiment for dose-dependent effect (Experiment 1), six nerve-ligated groups and six sham-operated groups with either oral saline or different doses of milnacipran were tested in both von Frey and radiant heat. In the experiment for time-course effect (Experiment 2), a nerve-ligated group and a sham-operated group were repeatedly scored with time in von Frey after oral 60 mg/kg milnacipran. On the next day, the same groups of mice were repeatedly scored with time in radiant heat. In the experiment for the effect of denervation (Experiment 3), three nerve-ligated groups and three sham-operated groups treated with either spinal saline or neurotoxins were tested with oral saline in both von Frey and radiant heat. After 3 h, the same groups of mice were tested with oral 60 mg/kg milnacipran. In comparison between the site of action (Experiment 4), 24 nerve-ligated groups and 24 sham-operated groups with either i.c.v., i.t. or local injection of saline or various doses of milnacipran. In open field (Experiment 5), five nerve-ligated groups and five sham-operated groups were tested with administration of saline or various doses of milnacipran.
All data are expressed as mean ± sd. Dose-dependent effect was assessed by analysis of variance (ANOVA) followed by Tukey-Kramer's test. Data on the time course of analgesic effect and the effect of administration route were assessed by ANOVA followed by Dunnett's test. The effect of neurotoxins was assessed by paired t-test and one way ANOVA. Statistical significance level was set at P < 0.05.
Seven days after nerve ligation, clear hypersensitivity to mechanical and thermal stimuli was observed compared with the preoperative state and the contralateral paw (Figs. 1 and 2). Milnacipran (p.o.) increased withdrawal threshold and withdrawal latency in nerve-ligated mice at doses between 30 and 120 mg/kg and increased withdrawal latency in sham-operated mice at doses between 15 and 120 mg/kg (P < 0.05 Dunnett's test). The effect was dose-dependent (Tukey-Kramer's test) but the effect of 120 mg/kg milnacipran was not different from that of 60 mg/kg milnacipran (P > 0.05; Student's t-test) (Fig. 1). Saline had no effect on either withdrawal threshold or withdrawal latency in sham and nerve-ligated mice.
In the von Frey test, milnacipran (60 mg/kg p.o.) significantly increased the withdrawal threshold of the ipsilateral paw between 40 and 160 min after p.o. administration compared with the preadministration baseline (0 min) (P < 0.05; Dunnett's test) although it did not change the withdrawal threshold of the contralateral paw (Fig. 2A). In the radiant heat test, milnacipran increased withdrawal latency of both ipsilateral and contralateral paws between 40 and 120 min and between 40 and 140 min, respectively compared with preadministration baseline (Fig. 2B).
To examine the involvement of spinal monoaminergic systems in the analgesic effect of milnacipran, spinal noradrenergic or serotonergic neurons were selectively denervated. The effects of chemical denervation on the contents of spinal NA, 5-HT and DA are shown in Table 1. 6-OHDA (i.t.) depleted the content of NA by more than 97% with only a slight (18%) but significant reduction of DA. 5,7-DHT reduced the content of 5-HT by more than 96% with no effect on NA or DA.
In the von Frey test (Fig. 3A), neither spinal noradrenergic nor serotonergic denervation modified the withdrawal threshold in sham mice. In nerve-ligated mice, although spinal noradrenergic denervation completely abolished the effect induced by 60 mg/kg milnacipran on withdrawal threshold, spinal serotonergic denervation did not affect the withdrawal threshold. In the radiant heat test (Fig. 3B), both spinal noradrenergic and serotonergic denervation reduced the withdrawal latency in sham mice (F2,21 = 26.3, †P < 0.0001). Both spinal noradrenergic and serotonergic denervation also reduced the effect of 60 mg/kg milnacipran on withdrawal latency in sham mice (F2,21 = 29.9, ‡P < 0.0001). In nerve-ligated mice, although spinal noradrenergic denervation completely abolished the effect induced by 60 mg/kg milnacipran on withdrawal latency, spinal serotonergic denervation did not affect the withdrawal latency.
The peak effect of milnacipran via i.c.v. and i.t. routes was observed between 10 and 20 min after injection in both sham and nerve-ligated mice (data not shown). Either i.c.v. or i.t. milnacipran increased withdrawal threshold and withdrawal latency at the doses between 0.7 and 21 μg per mouse and between 7 and 21 μg per mouse, respectively, in nerve-ligated mice (Fig. 4). In sham-operated mice, milnacipran administered i.c.v. or i.t. did not change withdrawal threshold although withdrawal latency was increased at doses between 0.7 and 21 μg per mouse and between 2.1 and 21 μg per mouse, respectively. Local administration of milnacipran had no effect in either test on either nerve-ligated or sham-operated mice until 90 min after injection (Fig. 4).
The locomotor activity was tested in the open field apparatus in sham and nerve-ligated mice. No difference in the distance traveled during the 10 min test was observed between the groups after the administration of up to 120 mg/kg p.o. milnacipran (Fig. 5).
The oral route and the doses for examining systemic effect of milnacipran were based on previous studies,43,44 which showed analgesic, antidepressant, and antianxiety effects at these doses. Because paw withdrawal can be influenced by the sedative effect, the possible induction of sedative effects by milnacipran was evaluated in naïve mice in an open field test. No reduction of locomotor activity was observed even at the highest doses of milnacipran. This is consistent with results reported by Mochizuki et al.44 and suggests the behavioral change induced by systemic and i.c.v. milnacipran may not be the result of a sedative effect.
Milnacipran increased the withdrawal latency in the radiant heat test in the contralateral paw of nerve-ligated mice and in sham-operated mice, suggesting that it induced an antinociceptive effect. The increased withdrawal threshold in the von Frey test and withdrawal latency in the radiant heat test in the injured paw, suggests that milnacipran also has antiallodynic and antihyperalgesic properties. The antinociceptive, antiallodynic, and antihyperalgesic effects of milnacipran were dose-dependent up to 60 mg/kg p.o. but the effect of 120 mg/kg p.o. was not significantly greater than that of 60 mg/kg (Fig. 1). Dose-dependent effects have been observed in studies that examined the effect of other analgesics, such as opioids and TCAs, on neuropathic pain induced by SNL.6,16,19,45 The efficacy of TCAs against allodynia, however, is controversial. Reports using the rat SNL model indicate that TCAs are effective against hyperalgesia but not against allodynia.6,19 In the present study, milnacipran had an effect on both allodynia and hyperalgesia induced by SNL in mice (Figs. 1 and 2).
In the experiment using neurotoxin, both spinal NA and 5-HT depletion slightly but significantly reduced the withdrawal latency in the radiant heat test, but not the withdrawal threshold in the von Frey test in sham-operated mice, (Fig. 3B), suggesting that both spinal NA and 5-HT neurons are involved in nociceptive transmission. On the other hand, spinal monoamine depletion did not further reduce the withdrawal threshold and latency induced by SNL in the tests. In other words, there appeared no worsening of allodynia and hyperalgesia after monoamine denervation although withdrawal threshold and latency were already low in nerve-ligated mice.
The antinociceptive effect of milnacipran, as measured by increases in withdrawal latency in sham-operated mice, was essentially unchanged after denervation of either NA or 5-HT (Fig. 3B) suggesting that its antinociceptive effect involves both noradrenergic and serotonergic neurotransmission.
Contrary to the antinociceptive effect, the antiallodynic and antihyperalgesic effects of milnacipran were attenuated by spinal NA denervation but not by 5-HT denervation. This suggests that the antiallodynic and antihyperalgesic effects of milnacipran are mediated principally through the spinal NA, but not 5-HT neurons, in nerve-ligated mice. These results are consistent with other reports investigating the effect of other analgesics in neuropathic pain induced by nerve injury, where spinal NA neurons appear to be involved to a greater extent in the antiallodynic and antihyperalgesic effects than spinal 5-HT neurons. A more important contribution of noradrenergic neurotransmission than serotonergic neurotransmission in the SNL model is suggested by the fact that the selective NA uptake inhibitors exhibit analgesic properties in neuropathic pain models, whereas selective 5-HT uptake inhibitors do not.6,8 Clinical studies have also shown analgesic and antiallodynic effects of antidepressants with a major noradrenergic component.23,46–48 On the contrary, Obata et al.34 reported the involvement of both NA and 5-HT in the antiallodynic effect of milnacipran in a rat neuropathic pain model. Although the exact mechanism of action of these antidepressants is still unknown, these results are consistent with our findings, suggesting the importance of noradrenergic systems in the antiallodynic and antihyperalgesic effect of these drugs.
In sham-operated mice, i.c.v. or i.t. but not local administration of milnacipran increased withdrawal latency in the radiant heat test, but did not increase withdrawal threshold in the von Frey test. This suggests that milnacipran's antinociceptive effect has its origin in the central nervous system. In ligated mice, antiallodynia and antihyperalgesia were observed after either i.t. or i.c.v. administration of milnacipran. Both antiallodynia and antihyperalgesia were dose-dependent. The site of analgesic action of TCA has been reported to be supraspinal, spinal and peripheral. Spinally injected TCAs inhibited biting and licking behaviors in a rat formalin test10 and spinal amitriptyline showed an antihyperalgesic effect in a rat SNL model.19 Korzeniewska-Rybicka and Plaznik20 suggested, however, that the supraspinal site is probably more important for the antinociceptive effect of imipramine and amitriptyline. On the other hand, spinally injected TCAs inhibited biting and licking behaviors in a rat formalin test10 and spinal amitriptyline showed antihyperalgesic effect in a rat spinal nerve ligation model.19 The peripheral action of TCAs has been well examined and characteristics other than monoaminergic uptake have been suggested. Amitriptyline and desipramine show the peripheral antinociceptive and antiallodynic effect, possibly by antiinflammation,49 by blocking sodium channels at peripheral sites,50,51 and by the action of adenosine.52,53 The involvement of NMDA receptors in spinal analgesia induced by TCAs has also been suggested, because TCAs have been shown to block NMDA receptors in high μM concentrations.25 On the other hand, milnacipran has been shown to block NMDA receptors in high μM concentrations.3 In our previous study, milnacipran blocked other ligand-gated ion channels, such as 5-HT3 and nACh receptors, in high μM concentrations but did not affect γ-aminobutyric acid type A (GABAA) receptors, even in high concentration.3 There are no studies investigating the potency of sodium channel blockers as opioid receptor blockers. It cannot be denied that no reaction by local injection of milnacipran always indicates lack of actions other than monoaminergic reuptake inhibition, because serotonin has been known to produce pronociception at peripheral site.54,55 Although more specific actions of milnacipran than TCAs might have less nonspecific effect, actions other than monoamine uptake inhibition are yet to be investigated.
In the present study, milnacipran had antinociceptive, antiallodynic, and antihyperalgesic effects in mice with SNL. Milnacipran has fewer side effects compared with amitriptyline and other TCAs, and may be useful as treatment for the relief of chronic pain, including conditions such as fibromyalgia.56
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