Neuroscience Letters 562 (2014) 28–33
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The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia Kumi Kaneko ∗ , Masato Umehara 1 , Takashi Homan 1 , Ken Okamoto 1 , Michiko Oka, Tatsuya Oyama Research Laboratories, Nippon Shinyaku Co., Ltd., 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan
h i g h l i g h t s • • • •
We compared the analgesic effects of tramadol in two kinds of chronic pain models. Oral treatment of tramadol improved partial sciatic nerve ligation-induced allodynia. Orally administered this drug also attenuated reserpine-induced tactile allodynia. The opioid system may be partly involved in the effect of tramadol on allodynia.
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Article history: Received 7 October 2013 Received in revised form 17 December 2013 Accepted 6 January 2014 Keywords: Tramadol Opioid Neuropathic pain Fibromyalgia Partial sciatic nerve ligation Reserpine Naloxone
a b s t r a c t (±)-Tramadol hydrochloride (tramadol) is a widely used analgesic for the treatment of cancer pain and chronic pain. Although many animal studies have shown antinociceptive effects of tramadol in both acute and chronic pain, little is known about the effect of tramadol in putative animal models of fibromyalgia. In this study, we compared the antiallodynic effects of oral administration of tramadol in two kinds of rat chronic pain models, neuropathic pain induced by partial sciatic nerve ligation (PSL) and reserpineinduced myalgia (RIM). In PSL rats, the threshold for responses induced by tactile stimulation with von Frey filaments was significantly decreased seven days after the operation, suggesting that the operation induced tactile allodynia. Orally administered tramadol showed a potent and dose-dependent antiallodynic effect on PSL-induced allodynia. In RIM rats, the threshold was significantly decreased five days after reserpine treatment. Orally administered tramadol also attenuated reserpine-induced tactile allodynia. To explore the mechanism of the antiallodynic effect of tramadol in RIM rats, we investigated the effect of the opioid antagonist naloxone on the tramadol-induced analgesic effect in these rats. The effect of tramadol was partially antagonized by naloxone, suggesting that the opioid receptor is involved at least in part in the antiallodynic effect of tramadol in RIM rats. These data indicate that orally administered tramadol produced improvement in both PSL rats and RIM rats at similar doses and provide evidence that the opioid system is partly involved in the analgesic effect of tramadol in RIM rats. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neuropathic pain is a chronic condition characterized by spontaneous burning pain, hyperalgesia, and allodynia and it is very difficult to manage [1]. To clarify its mechanisms and develop effective therapies, several potential animal models of neuropathic pain have been developed and studied [2]. Partial sciatic nerve ligation
Abbreviations: PSL, partial sciatic nerve ligation; RIM, reserpine-induced myalgia. ∗ Corresponding author. Tel.: +81 75 321 9179; fax: +81 75 314 3269. E-mail address: [email protected] (K. Kaneko). 1 These three authors contributed equally. 0304-3940/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2014.01.007
(PSL) is a well characterized rat model of neuropathic pain with sciatic nerve injury, and it exhibits tactile allodynia [3]. Fibromyalgia is a musculoskeletal disorder characterized by chronic widespread pain and various comorbid symptoms such as depression. Although the details of its pathophysiology are unknown, biogenic amine levels in the cerebrospinal fluid are significantly lower than normal in fibromyalgia patients, suggesting dysfunction of the descending analgesic neural pathway [4]. Because there are few consistently effective therapies for fibromyalgia, more-effective agents are eagerly awaited. Several potential animal models have been described [5–9], and a reserpine-induced myalgia (RIM) model that may mimic various aspects of fibromyalgia has recently been reported [8]. In the RIM model, reserpine induces long-lasting muscle hyperalgesia and tactile allodynia and markedly decreases monoamine levels in the
K. Kaneko et al. / Neuroscience Letters 562 (2014) 28–33
spinal cord and some regions of the brain. In addition, there is an increase in the immobility time in the forced-swim test, an indicator of depression, which is a frequent comorbid symptom in fibromyalgia patients. (±)-Tramadol hydrochloride (tramadol) is a widely used analgesic agent [10] that stimulates the -opioid receptor and inhibits serotonin and noradrenaline reuptake [11,12]. There are numerous animal studies on the antinociceptive effects of tramadol on heat pain [13] and chemical pain [14]. We have also recently demonstrated the effect of tramadol on visceral pain in rodent cystitis models [15]. However, few studies have been undertaken to investigate the effect of tramadol in putative experimental models of fibromyalgia. Therefore, we compared the mode of action of orally administered tramadol in PSL and RIM rats and investigated the mechanism of tramadol in RIM rats.
2. Materials and methods 2.1. Animals Male Sprague–Dawley rats (aged 5–6 weeks for PSL and 9 weeks for RIM at the beginning of the experiment; Japan SLC, Hamamatsu, Japan) were housed under controlled environmental conditions (23 ± 3 ◦ C; 12 h:12 h light–dark cycle, lights on at 08:00 h; free availability of food and water) for at least one week before use. The study was conducted in compliance with the Law for the Humane Treatment and Management of Animals (Law No. 105, 1 October 1973, as revised on 1 June 2006). All efforts were made to minimize animal suffering and to reduce the number of animals used. 2.2. Drugs Tramadol was kindly supplied by Grünenthal (Aachen, Germany). Reserpine and naloxone hydrochloride were purchased from Wako Pure Chemical Industries (Osaka, Japan) and Tocris Bioscience (Bristol, UK), respectively. Reserpine was dissolved in glacial acetic acid, diluted with distilled water to a final concentration of 0.5% acetic acid, and injected subcutaneously in a volume of 1 ml/kg. Naloxone was dissolved in saline and administered subcutaneously in 1 ml/kg and tramadol was dissolved in distilled water and administered intraperitoneally in 1 ml/kg or orally in 5 ml/kg. 2.3. PSL surgery PSL surgery was performed according to the method of Seltzer et al. [3]. Animals were anesthetized with pentobarbital. The right common sciatic nerve was exposed just distal to the branch leading to the posterior biceps femoris/semitendinosus muscle. The dorsal one-third to one-half of the sciatic nerve was tightly ligated with 8–0 silk suture and the wound was closed by suturing the muscle and skin layers. After recovering from the anesthesia, almost all animals showed guarding of the hind paw, but none engaged in autotomy. In sham-operated rats, the nerve was exposed but not ligated. To check the validity of the models, the tactile-response thresholds of all 10 PSL-operated rats were compared with those of five sham-operated rats seven days after surgery. The predrug tactile-response thresholds were measured first, and rats with a threshold of less than 5 g were selected for use in pharmacological tests as successful model rats. The selected rats were then allocated to four groups (n = 5 or 10/group), each of which received vehicle or tramadol. The tactile-response thresholds were again measured 1, 2 and 4 h after administration of vehicle or tramadol.
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2.4. Reserpine-induced myalgia RIM was produced in rats according to a previously reported protocol [8,16]. Briefly, reserpine was subcutaneously injected at a dose of 1 mg/kg once daily for three consecutive days. According to a previous study, food pellets were put on the floor of the cage after the reserpine injection as a nursing treatment so that the animals could access them more easily [16]. The baseline and time-course measurements of the tactile responses of seven RIM rats were compared with those of six sham-treated rats 1, 4, 7, 11 and 14 days after the last injection of reserpine. The effect of tramadol was evaluated five days after the last injection of reserpine. The predrug tactileresponse thresholds were measured first and rats with a threshold of less than 5 g were selected for use in pharmacological tests as successful model rats. The selected rats were then allocated to four groups (n = 10/group), each of which received vehicle or tramadol. The tactile-response thresholds were again measured 1, 2 and 4 h after administration of vehicle or tramadol. 2.5. von Frey hair test Tactile allodynia was measured by the up-down method as described previously [17]. Animals were individually placed on a wire-mesh floor and acclimatized to the environmental conditions for at least 30 min. After acclimatization, a tactile stimulus was applied to the middle plantar surface of the paw by placing one of a series of von Frey filaments (0.4, 0.6, 1.0, 2.0, 4.0, 6.0. 8.0 and 15.0 g) perpendicular to the surface of the paw. Testing was initiated with the 2.0-g filament. If this stimulus did not evoke a paw-withdrawal response, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was presented. Four additional responses were observed after the first response that changed from negative to positive or from positive to negative, and the 50% withdrawal threshold was determined. When continuous positive or negative responses were observed to the exhaustion of the stimulus set, values of 0.4 or 15.0 g, respectively, were assigned. 2.6. Statistical analysis Data were analyzed by using SAS version 9.1.3 (SAS Institute, Cary, NC, USA) and were expressed as the mean ± standard error (SEM). Differences in the tactile-response threshold between PSL or RIM rats and sham-treated rats and between rats treated with saline/tramadol and rats treated with naloxone/tramadol were analyzed for statistical significance by the Wilcoxon rank-sum test. Differences in the threshold between rats before and after naloxone/tramadol treatment were analyzed for statistical significance by the Wilcoxon signed-rank test. To evaluate the effect of tramadol on the threshold, differences between the vehicle-treated and tramadol-treated groups were analyzed for statistical significance by the Shirley–Williams test. P-values less than 0.05 were considered significant. 3. Results 3.1. Effect of tramadol on tactile allodynia in PSL rats We measured the withdrawal threshold of the ipsilateral paw seven days after PSL surgery and found that the mean threshold was markedly less than that of sham-operated rats (Fig. 1A), providing evidence that the operation had induced tactile allodynia. Intraperitoneally injected tramadol (10 and 30 mg/kg) significantly increased the mean threshold in a dose-dependent manner at 1 h after administration (Fig. 1B). Orally administered tramadol at the
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K. Kaneko et al. / Neuroscience Letters 562 (2014) 28–33
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Fig. 1. Effect of tramadol on tactile allodynia in PSL rats. (A) 50% withdrawal threshold of ipsilateral paw seven days after PSL. Sham: sham-operated rats (n = 5). PSL: partial sciatic nerve ligation (n = 10). Bars represent the mean ± SEM # P < 0.01 versus sham-operated rats (Wilcoxon rank-sum test). Effect of (B) intraperitoneally (n = 5) and (C) orally (n = 10) administered tramadol on 50% withdrawal threshold seven days after PSL. Each data point represents the mean ± SEM * P < 0.05, ** P < 0.01 versus vehicle-treated rats (Shirley–Williams test).
same doses significantly increased the threshold at 1–4 h after administration (Fig. 1C).
tramadol. The mean threshold of rats not treated with tramadol (Fig. 3A) did not change between pre and post naloxone treatment or between with and without naloxone treatment. Among the tramadol-treated groups (Fig. 3B–D), the mean threshold of naloxone-treated rats was lower than that of vehicle-treated rats. However, this threshold was still significantly higher than in rats before drug treatment. The changes in mean threshold between with and without naloxone treatment were significant at 3 and 30 mg/kg tramadol (Fig. 3B and D).
3.2. Effect of tramadol on tactile allodynia in RIM rats We measured the withdrawal threshold of the right paw on the indicated days after repeated subcutaneous injection of 1 mg/kg reserpine (once daily for three consecutive days). Consistent with the previous study [8], the mean threshold was significantly less than that of sham-treated rats from at least 1–14 days, and reached its lowest level during 4–7 days, after the last injection of reserpine (Fig. 2A). Therefore pharmacological tests were performed five days after the last injection of reserpine. Orally administered tramadol (3, 10 and 30 mg/kg) significantly increased the mean threshold in a dose-dependent manner at 1–4 h after administration (Fig. 2B).
4. Discussion In this study, we compared the antiallodynic effect of tramadol in two kinds of animal chronic pain models, PSL and RIM. PSL is a well characterized rat model of neuropathic pain with sciatic nerve injury [3], and it exhibits tactile allodynia. In agreement with an earlier report [3], the mean tactile-response threshold of PSL rats in the present study was significantly less than that of sham-treated rats seven days after surgery. In neuropathic pain models, the effects of intraperitoneally [18,19] or subcutaneously [20] injected tramadol have been reported, but, to our knowledge, the effect of orally administered tramadol has not been studied
3.3. Effect of opioid antagonist naloxone on antiallodynic effect of tramadol in RIM rats Naloxone (1 mg/kg) was subcutaneously injected 5 min prior to the oral administration of tramadol (3, 10 or 30 mg/kg; Fig. 3). Pawwithdrawal thresholds were determined 1 h after administration of
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Fig. 2. Effect of tramadol on tactile allodynia in RIM rats. (A) Time courses of 50% withdrawal threshold associated with repeated subcutaneous injection of 1 mg/kg reserpine (once daily for three consecutive days). The withdrawal threshold of the right paw was measured with the von Frey filament test on the indicated days. Sham: sham-treated rats (n = 6). Reserpine: reserpine-treated rats (n = 7). Each data point represents the mean ± SEM # P < 0.05, ## P < 0.01, versus sham-treated rats (Wilcoxon rank-sum test). (B) Effect of orally administered tramadol on 50% withdrawal threshold five days after the last injection of reserpine. Each data point represents the mean ± SEM (n = 10). * P < 0.05, ** P < 0.01, versus vehicle-treated control rats (Shirley–Williams test).
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K. Kaneko et al. / Neuroscience Letters 562 (2014) 28–33
P = 0.3750 P = 0.2244
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Fig. 3. Effect of opioid antagonist naloxone on the antiallodynic effect of vehicle (sterilized water; A), and 3 mg/kg (B), 10 mg/kg (C) and 30 mg/kg tramadol (D) in RIM rats. Withdrawal thresholds were measured with the von Frey filament test five days after the last injection of reserpine. Each data point represents the mean ± SEM (n = 10). Numerical values represent the P-value versus rats treated with saline and tramadol (Wilcoxon rank-sum test) or rats before treatment (Wilcoxon signed-rank test).
(oral is the clinical administration route). Therefore, we evaluated the effect of oral and intraperitoneal tramadol on neuropathic allodynia in PSL rats. We showed firstly that not only intraperitoneal but also oral administration of tramadol significantly increased the mean tactile-response threshold at 1 h after administration at around the same dosages. The effective doses of tramadol in the present study (10 and 30 mg/kg) were almost the same as those reported to be effective by Apaydin et al. [18], who administered the drug intraperitoneally in a similar rat model of neuropathic pain. We next investigated the effect of tramadol in RIM rats. RIM is a model that shows long-lasting muscle hyperalgesia and tactile allodynia, decreases in monoamine levels in several brain regions, and increases in immobility time in the forced-swim test, and it is a potential animal model of fibromyalgia. The pharmacological validation of this model shows its close analogy to fibromyalgia in that the model mimics the clinical therapeutic situation in fibromyalgia patients; that is, tactile allodynia and/or muscular hyperalgesia is attenuated by pregabalin, duloxetine, and pramipexole, which are analgesics with clinical efficacy, but not by diclofenac, a nonsteroidal anti-inflammatory drug with limited clinical efficacy [8]. In the present study, we have shown for the first time that tramadol alone attenuated tactile allodynia in this model, although a previous study reported the efficacy of the combined use of tramadol and milnacipran in another rat model of fibromyalgia [21]. Many clinical studies have demonstrated the efficacy of tramadol in the management of cancer pain [22,23], neuropathic pain
[24–26] and fibromyalgia [27,28]. The daily clinical dose range of 2–6 mg/kg tramadol used for the treatment of cancer pain and chronic pain overlaps the experimental dose range of 3–30 mg/kg daily used in the present animal study. Therefore the antiallodynic action of tramadol in the present study suggests that it would have clinical potency in the treatment of chronic neuropathic pain and fibromyalgia. In addition, the antiallodynic effects of tramadol in RIM models seemed to be stronger and longer-lasting than in the PSL model. Although the differences were small, the clinical efficacy of tramadol may be greater in fibromyalgia than in neuropathic pain. The mechanisms of the tramadol-induced antiallodynic effect have been well investigated in neuropathic pain models. The effect is partially antagonized by naloxone [18], suggesting that it may be partly mediated by opioid (naloxone-sensitive) receptors. In addition, serotonergic and noradrenergic neurons have also been suggested to be involved in the effect of tramadol on neuropathic allodynia [19,20]. Although many studies suggest that dysfunction of the serotonergic and noradrenergic systems may be involved in fibromyalgia and RIM rats [4,8,29–31], there are no reports of the involvement of opioid systems in RIM rats. Therefore we examined the involvement of opioid systems, and showed that in RIM rats the tramadol-induced antiallodynic effect was significantly antagonized by the administration of naloxone. This is the first evidence that the effect of tramadol in RIM rats is mediated in part by opioid mechanisms. Although several studies report that opioids are relatively ineffective against fibromyalgia [32,33], some fibromyalgia patients do respond to intravenous administration
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of morphine [34]. In a study in rats, morphine weakly but significantly attenuated subdiaphragmatic vagotomy-induced pain, which is somewhat similar to the symptoms of fibromyalgia [9]. The antagonist effect of naloxone in RIM rats observed in the present study is consistent with the above evidence of the involvement of opioid systems in fibromyalgia or in a fibromyalgia model rat. However, central -opioid receptor availability is reported to be decreased in some fibromyalgia patients [35]. Therefore, further studies are needed to clarify the involvement of the opioid system in the RIM model. In addition, we investigated the effect of the specific ␣2 adrenoceptor antagonist yohimbine on the effect of tramadol in RIM rats. The mean threshold in rats injected subcutaneously with yohimbine (3 mg/kg) 15 min prior to oral administration of tramadol (10 mg/kg) was lower (though not significantly lower) than in rats treated with 5% glucose prior to tramadol (the mean threshold 1 h after administration of tramadol was 10.53 ± 3.04 g, compared to 11.67 ± 1.67 g with glucose treatment; n = 3). We are not sure why we did not obtain a clear result with yohimbine, but it may be due to the fact that various receptors play a role in serotonergic and noradrenergic systems. Many reports have demonstrated the involvement of serotonergic and noradrenergic systems in the effect of tramadol in other chronic pain models [19,20], and serotonin 2C receptor agonists are known to attenuate muscular hyperalgesia in the RIM model [16]. We have also shown a significant effect of intraperitoneally administered duloxetine (30 mg/kg), a serotonin and noradrenaline reuptake inhibitor, on the tactile allodynia in RIM rats (the mean threshold 1 h after administration was 11.36 ± 1.58 g, compared to 5.63 ± 1.84 g with glucose treatment; P < 0.05; Wilcoxon rank-sum test; n = 8). Therefore, it is likely that multiple mechanisms of tramadol involving, for example, opioid, serotonergic and noradrenergic systems, work with different efficacies and that a combination of these mechanisms is responsible for the antiallodynic effect of tramadol. 5. Conclusions Orally and intraperitoneally administered tramadol markedly increased the tactile-response threshold in PSL rats. Tramadol also had an antiallodynic effect on the tactile allodynia of RIM rats, and this effect was partially antagonized by the opioid antagonist naloxone. Tramadol may be a useful treatment for neuropathic pain and fibromyalgia, and both opioid and non-opioid mechanisms may be responsible for its effects. Conflict of interest We have no disclosure to report. Acknowledgment We thank Dr Gerald E. Smyth and Mr. Masaru Tamura, Nippon Shinyaku Co., Ltd, for useful suggestions during the preparation of the manuscript and assistance in the statistical analysis of the data, respectively. References [1] R. Maag, R. Baron, Neuropathic pain: translational research and impact for patient care, Curr. Pain Headache Rep. 10 (2006) 191–198. [2] A.S. Jaggi, V. Jain, N. Singh, Animal models of neuropathic pain, Fundam. Clin. Pharmacol. 25 (2011) 1–28. [3] Z. Seltzer, R. Dubner, Y. Shir, A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury, Pain 43 (1990) 205–218.
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The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia Kumi Kaneko ∗ , Masato Umehara 1 , Takashi Homan 1 , Ken Okamoto 1 , Michiko Oka, Tatsuya Oyama Research Laboratories, Nippon Shinyaku Co., Ltd., 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan
h i g h l i g h t s • • • •
We compared the analgesic effects of tramadol in two kinds of chronic pain models. Oral treatment of tramadol improved partial sciatic nerve ligation-induced allodynia. Orally administered this drug also attenuated reserpine-induced tactile allodynia. The opioid system may be partly involved in the effect of tramadol on allodynia.
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Article history: Received 7 October 2013 Received in revised form 17 December 2013 Accepted 6 January 2014 Keywords: Tramadol Opioid Neuropathic pain Fibromyalgia Partial sciatic nerve ligation Reserpine Naloxone
a b s t r a c t (±)-Tramadol hydrochloride (tramadol) is a widely used analgesic for the treatment of cancer pain and chronic pain. Although many animal studies have shown antinociceptive effects of tramadol in both acute and chronic pain, little is known about the effect of tramadol in putative animal models of fibromyalgia. In this study, we compared the antiallodynic effects of oral administration of tramadol in two kinds of rat chronic pain models, neuropathic pain induced by partial sciatic nerve ligation (PSL) and reserpineinduced myalgia (RIM). In PSL rats, the threshold for responses induced by tactile stimulation with von Frey filaments was significantly decreased seven days after the operation, suggesting that the operation induced tactile allodynia. Orally administered tramadol showed a potent and dose-dependent antiallodynic effect on PSL-induced allodynia. In RIM rats, the threshold was significantly decreased five days after reserpine treatment. Orally administered tramadol also attenuated reserpine-induced tactile allodynia. To explore the mechanism of the antiallodynic effect of tramadol in RIM rats, we investigated the effect of the opioid antagonist naloxone on the tramadol-induced analgesic effect in these rats. The effect of tramadol was partially antagonized by naloxone, suggesting that the opioid receptor is involved at least in part in the antiallodynic effect of tramadol in RIM rats. These data indicate that orally administered tramadol produced improvement in both PSL rats and RIM rats at similar doses and provide evidence that the opioid system is partly involved in the analgesic effect of tramadol in RIM rats. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neuropathic pain is a chronic condition characterized by spontaneous burning pain, hyperalgesia, and allodynia and it is very difficult to manage [1]. To clarify its mechanisms and develop effective therapies, several potential animal models of neuropathic pain have been developed and studied [2]. Partial sciatic nerve ligation
Abbreviations: PSL, partial sciatic nerve ligation; RIM, reserpine-induced myalgia. ∗ Corresponding author. Tel.: +81 75 321 9179; fax: +81 75 314 3269. E-mail address: [email protected] (K. Kaneko). 1 These three authors contributed equally. 0304-3940/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2014.01.007
(PSL) is a well characterized rat model of neuropathic pain with sciatic nerve injury, and it exhibits tactile allodynia [3]. Fibromyalgia is a musculoskeletal disorder characterized by chronic widespread pain and various comorbid symptoms such as depression. Although the details of its pathophysiology are unknown, biogenic amine levels in the cerebrospinal fluid are significantly lower than normal in fibromyalgia patients, suggesting dysfunction of the descending analgesic neural pathway [4]. Because there are few consistently effective therapies for fibromyalgia, more-effective agents are eagerly awaited. Several potential animal models have been described [5–9], and a reserpine-induced myalgia (RIM) model that may mimic various aspects of fibromyalgia has recently been reported [8]. In the RIM model, reserpine induces long-lasting muscle hyperalgesia and tactile allodynia and markedly decreases monoamine levels in the
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spinal cord and some regions of the brain. In addition, there is an increase in the immobility time in the forced-swim test, an indicator of depression, which is a frequent comorbid symptom in fibromyalgia patients. (±)-Tramadol hydrochloride (tramadol) is a widely used analgesic agent [10] that stimulates the -opioid receptor and inhibits serotonin and noradrenaline reuptake [11,12]. There are numerous animal studies on the antinociceptive effects of tramadol on heat pain [13] and chemical pain [14]. We have also recently demonstrated the effect of tramadol on visceral pain in rodent cystitis models [15]. However, few studies have been undertaken to investigate the effect of tramadol in putative experimental models of fibromyalgia. Therefore, we compared the mode of action of orally administered tramadol in PSL and RIM rats and investigated the mechanism of tramadol in RIM rats.
2. Materials and methods 2.1. Animals Male Sprague–Dawley rats (aged 5–6 weeks for PSL and 9 weeks for RIM at the beginning of the experiment; Japan SLC, Hamamatsu, Japan) were housed under controlled environmental conditions (23 ± 3 ◦ C; 12 h:12 h light–dark cycle, lights on at 08:00 h; free availability of food and water) for at least one week before use. The study was conducted in compliance with the Law for the Humane Treatment and Management of Animals (Law No. 105, 1 October 1973, as revised on 1 June 2006). All efforts were made to minimize animal suffering and to reduce the number of animals used. 2.2. Drugs Tramadol was kindly supplied by Grünenthal (Aachen, Germany). Reserpine and naloxone hydrochloride were purchased from Wako Pure Chemical Industries (Osaka, Japan) and Tocris Bioscience (Bristol, UK), respectively. Reserpine was dissolved in glacial acetic acid, diluted with distilled water to a final concentration of 0.5% acetic acid, and injected subcutaneously in a volume of 1 ml/kg. Naloxone was dissolved in saline and administered subcutaneously in 1 ml/kg and tramadol was dissolved in distilled water and administered intraperitoneally in 1 ml/kg or orally in 5 ml/kg. 2.3. PSL surgery PSL surgery was performed according to the method of Seltzer et al. [3]. Animals were anesthetized with pentobarbital. The right common sciatic nerve was exposed just distal to the branch leading to the posterior biceps femoris/semitendinosus muscle. The dorsal one-third to one-half of the sciatic nerve was tightly ligated with 8–0 silk suture and the wound was closed by suturing the muscle and skin layers. After recovering from the anesthesia, almost all animals showed guarding of the hind paw, but none engaged in autotomy. In sham-operated rats, the nerve was exposed but not ligated. To check the validity of the models, the tactile-response thresholds of all 10 PSL-operated rats were compared with those of five sham-operated rats seven days after surgery. The predrug tactile-response thresholds were measured first, and rats with a threshold of less than 5 g were selected for use in pharmacological tests as successful model rats. The selected rats were then allocated to four groups (n = 5 or 10/group), each of which received vehicle or tramadol. The tactile-response thresholds were again measured 1, 2 and 4 h after administration of vehicle or tramadol.
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2.4. Reserpine-induced myalgia RIM was produced in rats according to a previously reported protocol [8,16]. Briefly, reserpine was subcutaneously injected at a dose of 1 mg/kg once daily for three consecutive days. According to a previous study, food pellets were put on the floor of the cage after the reserpine injection as a nursing treatment so that the animals could access them more easily [16]. The baseline and time-course measurements of the tactile responses of seven RIM rats were compared with those of six sham-treated rats 1, 4, 7, 11 and 14 days after the last injection of reserpine. The effect of tramadol was evaluated five days after the last injection of reserpine. The predrug tactileresponse thresholds were measured first and rats with a threshold of less than 5 g were selected for use in pharmacological tests as successful model rats. The selected rats were then allocated to four groups (n = 10/group), each of which received vehicle or tramadol. The tactile-response thresholds were again measured 1, 2 and 4 h after administration of vehicle or tramadol. 2.5. von Frey hair test Tactile allodynia was measured by the up-down method as described previously [17]. Animals were individually placed on a wire-mesh floor and acclimatized to the environmental conditions for at least 30 min. After acclimatization, a tactile stimulus was applied to the middle plantar surface of the paw by placing one of a series of von Frey filaments (0.4, 0.6, 1.0, 2.0, 4.0, 6.0. 8.0 and 15.0 g) perpendicular to the surface of the paw. Testing was initiated with the 2.0-g filament. If this stimulus did not evoke a paw-withdrawal response, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was presented. Four additional responses were observed after the first response that changed from negative to positive or from positive to negative, and the 50% withdrawal threshold was determined. When continuous positive or negative responses were observed to the exhaustion of the stimulus set, values of 0.4 or 15.0 g, respectively, were assigned. 2.6. Statistical analysis Data were analyzed by using SAS version 9.1.3 (SAS Institute, Cary, NC, USA) and were expressed as the mean ± standard error (SEM). Differences in the tactile-response threshold between PSL or RIM rats and sham-treated rats and between rats treated with saline/tramadol and rats treated with naloxone/tramadol were analyzed for statistical significance by the Wilcoxon rank-sum test. Differences in the threshold between rats before and after naloxone/tramadol treatment were analyzed for statistical significance by the Wilcoxon signed-rank test. To evaluate the effect of tramadol on the threshold, differences between the vehicle-treated and tramadol-treated groups were analyzed for statistical significance by the Shirley–Williams test. P-values less than 0.05 were considered significant. 3. Results 3.1. Effect of tramadol on tactile allodynia in PSL rats We measured the withdrawal threshold of the ipsilateral paw seven days after PSL surgery and found that the mean threshold was markedly less than that of sham-operated rats (Fig. 1A), providing evidence that the operation had induced tactile allodynia. Intraperitoneally injected tramadol (10 and 30 mg/kg) significantly increased the mean threshold in a dose-dependent manner at 1 h after administration (Fig. 1B). Orally administered tramadol at the
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Fig. 1. Effect of tramadol on tactile allodynia in PSL rats. (A) 50% withdrawal threshold of ipsilateral paw seven days after PSL. Sham: sham-operated rats (n = 5). PSL: partial sciatic nerve ligation (n = 10). Bars represent the mean ± SEM # P < 0.01 versus sham-operated rats (Wilcoxon rank-sum test). Effect of (B) intraperitoneally (n = 5) and (C) orally (n = 10) administered tramadol on 50% withdrawal threshold seven days after PSL. Each data point represents the mean ± SEM * P < 0.05, ** P < 0.01 versus vehicle-treated rats (Shirley–Williams test).
same doses significantly increased the threshold at 1–4 h after administration (Fig. 1C).
tramadol. The mean threshold of rats not treated with tramadol (Fig. 3A) did not change between pre and post naloxone treatment or between with and without naloxone treatment. Among the tramadol-treated groups (Fig. 3B–D), the mean threshold of naloxone-treated rats was lower than that of vehicle-treated rats. However, this threshold was still significantly higher than in rats before drug treatment. The changes in mean threshold between with and without naloxone treatment were significant at 3 and 30 mg/kg tramadol (Fig. 3B and D).
3.2. Effect of tramadol on tactile allodynia in RIM rats We measured the withdrawal threshold of the right paw on the indicated days after repeated subcutaneous injection of 1 mg/kg reserpine (once daily for three consecutive days). Consistent with the previous study [8], the mean threshold was significantly less than that of sham-treated rats from at least 1–14 days, and reached its lowest level during 4–7 days, after the last injection of reserpine (Fig. 2A). Therefore pharmacological tests were performed five days after the last injection of reserpine. Orally administered tramadol (3, 10 and 30 mg/kg) significantly increased the mean threshold in a dose-dependent manner at 1–4 h after administration (Fig. 2B).
4. Discussion In this study, we compared the antiallodynic effect of tramadol in two kinds of animal chronic pain models, PSL and RIM. PSL is a well characterized rat model of neuropathic pain with sciatic nerve injury [3], and it exhibits tactile allodynia. In agreement with an earlier report [3], the mean tactile-response threshold of PSL rats in the present study was significantly less than that of sham-treated rats seven days after surgery. In neuropathic pain models, the effects of intraperitoneally [18,19] or subcutaneously [20] injected tramadol have been reported, but, to our knowledge, the effect of orally administered tramadol has not been studied
3.3. Effect of opioid antagonist naloxone on antiallodynic effect of tramadol in RIM rats Naloxone (1 mg/kg) was subcutaneously injected 5 min prior to the oral administration of tramadol (3, 10 or 30 mg/kg; Fig. 3). Pawwithdrawal thresholds were determined 1 h after administration of
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Fig. 2. Effect of tramadol on tactile allodynia in RIM rats. (A) Time courses of 50% withdrawal threshold associated with repeated subcutaneous injection of 1 mg/kg reserpine (once daily for three consecutive days). The withdrawal threshold of the right paw was measured with the von Frey filament test on the indicated days. Sham: sham-treated rats (n = 6). Reserpine: reserpine-treated rats (n = 7). Each data point represents the mean ± SEM # P < 0.05, ## P < 0.01, versus sham-treated rats (Wilcoxon rank-sum test). (B) Effect of orally administered tramadol on 50% withdrawal threshold five days after the last injection of reserpine. Each data point represents the mean ± SEM (n = 10). * P < 0.05, ** P < 0.01, versus vehicle-treated control rats (Shirley–Williams test).
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P = 0.3750 P = 0.2244
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Fig. 3. Effect of opioid antagonist naloxone on the antiallodynic effect of vehicle (sterilized water; A), and 3 mg/kg (B), 10 mg/kg (C) and 30 mg/kg tramadol (D) in RIM rats. Withdrawal thresholds were measured with the von Frey filament test five days after the last injection of reserpine. Each data point represents the mean ± SEM (n = 10). Numerical values represent the P-value versus rats treated with saline and tramadol (Wilcoxon rank-sum test) or rats before treatment (Wilcoxon signed-rank test).
(oral is the clinical administration route). Therefore, we evaluated the effect of oral and intraperitoneal tramadol on neuropathic allodynia in PSL rats. We showed firstly that not only intraperitoneal but also oral administration of tramadol significantly increased the mean tactile-response threshold at 1 h after administration at around the same dosages. The effective doses of tramadol in the present study (10 and 30 mg/kg) were almost the same as those reported to be effective by Apaydin et al. [18], who administered the drug intraperitoneally in a similar rat model of neuropathic pain. We next investigated the effect of tramadol in RIM rats. RIM is a model that shows long-lasting muscle hyperalgesia and tactile allodynia, decreases in monoamine levels in several brain regions, and increases in immobility time in the forced-swim test, and it is a potential animal model of fibromyalgia. The pharmacological validation of this model shows its close analogy to fibromyalgia in that the model mimics the clinical therapeutic situation in fibromyalgia patients; that is, tactile allodynia and/or muscular hyperalgesia is attenuated by pregabalin, duloxetine, and pramipexole, which are analgesics with clinical efficacy, but not by diclofenac, a nonsteroidal anti-inflammatory drug with limited clinical efficacy [8]. In the present study, we have shown for the first time that tramadol alone attenuated tactile allodynia in this model, although a previous study reported the efficacy of the combined use of tramadol and milnacipran in another rat model of fibromyalgia [21]. Many clinical studies have demonstrated the efficacy of tramadol in the management of cancer pain [22,23], neuropathic pain
[24–26] and fibromyalgia [27,28]. The daily clinical dose range of 2–6 mg/kg tramadol used for the treatment of cancer pain and chronic pain overlaps the experimental dose range of 3–30 mg/kg daily used in the present animal study. Therefore the antiallodynic action of tramadol in the present study suggests that it would have clinical potency in the treatment of chronic neuropathic pain and fibromyalgia. In addition, the antiallodynic effects of tramadol in RIM models seemed to be stronger and longer-lasting than in the PSL model. Although the differences were small, the clinical efficacy of tramadol may be greater in fibromyalgia than in neuropathic pain. The mechanisms of the tramadol-induced antiallodynic effect have been well investigated in neuropathic pain models. The effect is partially antagonized by naloxone [18], suggesting that it may be partly mediated by opioid (naloxone-sensitive) receptors. In addition, serotonergic and noradrenergic neurons have also been suggested to be involved in the effect of tramadol on neuropathic allodynia [19,20]. Although many studies suggest that dysfunction of the serotonergic and noradrenergic systems may be involved in fibromyalgia and RIM rats [4,8,29–31], there are no reports of the involvement of opioid systems in RIM rats. Therefore we examined the involvement of opioid systems, and showed that in RIM rats the tramadol-induced antiallodynic effect was significantly antagonized by the administration of naloxone. This is the first evidence that the effect of tramadol in RIM rats is mediated in part by opioid mechanisms. Although several studies report that opioids are relatively ineffective against fibromyalgia [32,33], some fibromyalgia patients do respond to intravenous administration
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of morphine [34]. In a study in rats, morphine weakly but significantly attenuated subdiaphragmatic vagotomy-induced pain, which is somewhat similar to the symptoms of fibromyalgia [9]. The antagonist effect of naloxone in RIM rats observed in the present study is consistent with the above evidence of the involvement of opioid systems in fibromyalgia or in a fibromyalgia model rat. However, central -opioid receptor availability is reported to be decreased in some fibromyalgia patients [35]. Therefore, further studies are needed to clarify the involvement of the opioid system in the RIM model. In addition, we investigated the effect of the specific ␣2 adrenoceptor antagonist yohimbine on the effect of tramadol in RIM rats. The mean threshold in rats injected subcutaneously with yohimbine (3 mg/kg) 15 min prior to oral administration of tramadol (10 mg/kg) was lower (though not significantly lower) than in rats treated with 5% glucose prior to tramadol (the mean threshold 1 h after administration of tramadol was 10.53 ± 3.04 g, compared to 11.67 ± 1.67 g with glucose treatment; n = 3). We are not sure why we did not obtain a clear result with yohimbine, but it may be due to the fact that various receptors play a role in serotonergic and noradrenergic systems. Many reports have demonstrated the involvement of serotonergic and noradrenergic systems in the effect of tramadol in other chronic pain models [19,20], and serotonin 2C receptor agonists are known to attenuate muscular hyperalgesia in the RIM model [16]. We have also shown a significant effect of intraperitoneally administered duloxetine (30 mg/kg), a serotonin and noradrenaline reuptake inhibitor, on the tactile allodynia in RIM rats (the mean threshold 1 h after administration was 11.36 ± 1.58 g, compared to 5.63 ± 1.84 g with glucose treatment; P < 0.05; Wilcoxon rank-sum test; n = 8). Therefore, it is likely that multiple mechanisms of tramadol involving, for example, opioid, serotonergic and noradrenergic systems, work with different efficacies and that a combination of these mechanisms is responsible for the antiallodynic effect of tramadol. 5. Conclusions Orally and intraperitoneally administered tramadol markedly increased the tactile-response threshold in PSL rats. Tramadol also had an antiallodynic effect on the tactile allodynia of RIM rats, and this effect was partially antagonized by the opioid antagonist naloxone. Tramadol may be a useful treatment for neuropathic pain and fibromyalgia, and both opioid and non-opioid mechanisms may be responsible for its effects. Conflict of interest We have no disclosure to report. Acknowledgment We thank Dr Gerald E. Smyth and Mr. Masaru Tamura, Nippon Shinyaku Co., Ltd, for useful suggestions during the preparation of the manuscript and assistance in the statistical analysis of the data, respectively. References [1] R. Maag, R. Baron, Neuropathic pain: translational research and impact for patient care, Curr. Pain Headache Rep. 10 (2006) 191–198. [2] A.S. Jaggi, V. Jain, N. Singh, Animal models of neuropathic pain, Fundam. Clin. Pharmacol. 25 (2011) 1–28. [3] Z. Seltzer, R. Dubner, Y. Shir, A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury, Pain 43 (1990) 205–218.
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