- Email: [email protected]
Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy
Neuroscience Letters 368 (2004) 341–344
Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy Seung Keun Back, Sang Youn Won, Seung Kil Hong, Heung Sik Na∗ Department of Physiology, Medical Science Research Center, Korea University College of Medicine, 126-1 Anam-dong 5 Ga, Sungbuk-Gu, Seoul 136-705, Korea Received 24 May 2004; received in revised form 30 July 2004; accepted 31 July 2004
Abstract Although recent studies demonstrated the relieving effect of gabapentin on neuropathic pain, the effect has not been sufficiently examined. In the present study, we investigated the effect of gabapentin on mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Under enflurane anesthesia, animals were subjected to the partial injury of the nerves innervating the tail. Behavioral tests for mechanical, cold and warm allodynia on the tail were performed by von Frey hair (2.0 g) stimulation, 4 and 40 ◦ C water immersion, respectively. Intraperitoneal injection of gabapentin (30, 100, 300 mg/kg) significantly alleviated mechanical, warm and cold allodynia in a dose-dependent manner. Our results suggest that gabapentin is an effective agent against mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Neuropathic pain; Gabapentin; Peripheral neuropathy; Allodynia
Peripheral nerve injury often results in chronic neuropathic pain syndromes such as spontaneous burning pain, hyperalgesia and allodynia [5,17,21]. Neuropathic pains are often poorly treated by currently available medications; opioids [2] and non-steroidal anti-inflammatory drugs [14]. Recently, anticonvulsant gabapentin is widely becoming accepted as an alternative therapeutic agent for neuropathic pain [18]. However, despite the possibility that individual neuropathic signs resulting from particular pathomechanisms may require different management strategies, the effect of gabapentin against neuropathic pain has not been extensively examined. In addition, although gabapentin has significantly alleviated mechanical allodynia and heat hyperalgesia in neuropathic animals [1,7] as well as in patients with neuropathy [3,15,19], the analgesic effect on cold allodynia remains controversial [6,9,11,23,24]. In the present study, we investigated the effect of gabapentin on mechanical, warm and cold of allodynia in a rat model of peripheral neuropathy. As far as we know, ∗ Corresponding author. Tel.: +82 2 920 6188; fax: +82 2 925 5492. E-mail address: [email protected] (H.S. Na).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.07.091
this is the first report on the simultaneous examination of the analgesic effect of gabapentin on mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Young adult male Sprague–Dawley rats (150–200 g, n = 60) were used in this study. The neuropathic surgery was based on the procedure previously described by Sung et al. [20]. In brief, under enflurane anesthesia (0.5–2.0%) animals were subjected to the unilateral transection of the superior caudal trunk at the level between the S3 and S4 spinal nerve. This surgery partially injured the S1–S3 spinal nerves innervating the tail. To monitor the generation of neuropathic pain, the behavioral tests for mechanical, cold and warm allodynia were carried out in all experimental animals 1 day prior to and 1, 7 and 14 day(s) after nerve injury. As reported previously [12], mechanical allodynia was assessed by the tail-withdrawal response following poking the tail with a von Frey hair (bending force 2.0 g). The most sensitive spot of the tail was first determined by rubbing or poking various areas of the tail systematically with the von Frey hair. Then, this spot was challenged 10 times with 5–10 s intervals with the von Frey hair. The occurrence of tail withdrawal, in response to the
342
S.K. Back et al. / Neuroscience Letters 368 (2004) 341–344
indentation of the rat tail skin with the hair, was expressed as a percentage of trials. The tests for cold and warm allodynia were performed by immersing the tail into cold (4 ◦ C) or warm (40 ◦ C) water, respectively, measuring the latency of tail withdrawal or twitch, within a cut-off time of 15 s. The tests for cold and warm allodynia were repeated five times with 5 min intervals. The average latency of tail response was calculated. After behavioral tests on post-surgery day 14, gabapentin (30, 100 or 300 mg/kg, Sigma, St. Louis, MO, USA) or saline vehicle were administered intraperitoneally. Thereafter, behavioral tests for mechanical, cold and warm allodynia were performed at 1, 3, 5 h and 1, 2 days after the injection. We also examined if a noxious pinprick applied to the tail could evoke a tail-withdrawal response after gabapentin injection in intact animals (n = 5), without peripheral nerve injury. The pinprick test was repeated 10 times at a 10–20 s interval to determine the response frequency. Behavioral data of the present study were obtained in a blind fashion; the investigators who conducted behavioral experiments were unaware of the injection status of the rats, and those who performed the injection were unaware of the behavioral results. Data are expressed as mean ± S.E.M. Statistical analysis was conducted with the Friedman repeated measures ANOVA followed by a pairwise comparison of pain behaviors between pre- and post-injection, utilizing a Dunnett’s t-test on the ranked data. P < 0.05 was considered to be significant. Before nerve injury, animals rarely exhibited tailwithdrawal responses to von Frey hair, cold (4 ◦ C) and warm (40 ◦ C) water stimuli (Figs. 1–3). However, post-operative animals showed significantly increased tail-withdrawal frequency to von Frey hair stimulation (P < 0.05) and markedly decreased tail-withdrawal latencies to cold or warm water stimuli (P < 0.05, respectively). These sensory abnormalities are widely accepted as signs of mechanical, cold and warm allodynia. Figs. 1–3 illustrate that gabapentin administered intraperitoneally on post-surgery day 14 significantly alleviated the mechanical, warm and cold allodynia, respectively, in a dosedependent manner, with a maximal effect between 1 and 3 h after the injection (P < 0.05, Dunnett’s t-test). The highest dose of gabapentin (300 mg/kg) completely alleviated the mechanical and warm allodynia, and this antiallodynic effect lasted for a day after the injection. However, cold allodynia was less sensitive to gabapentin than mechanical and warm allodynia (Figs. 1–3). No effect on the allodynia was observed in animals injected with the saline vehicle. In order to test for normal reflex behavior in the presence of drug, a noxious mechanical (pinprick) stimulus was applied to the tail skin of normal animal. The pinprick induced a tailwithdrawal response, accompanied by vocalization in >90% of the trials even 1 h after the injection of the highest dose (300 mg/kg, data not shown). The present results show that gabapentin significantly alleviated in rat the mechanical, warm and cold of allodynia in
Fig. 1. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on mechanical allodynia. Mean (±S.E.M.) response frequencies to 10 applications of a von Frey hair (19.6 mN, 2.0 g) on the tail skin are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes a response frequency that is significantly different from N14 (P < 0.05).
a dose-dependent manner, with a maximal effect between 1 and 3 h after the injection. In line with the present results, previous studies demonstrated that gabapentin significantly attenuates neuropathic pain behavior in several animal models of peripheral neuropathy. Hwang and Yaksh [10], and Abdi et al. [1]
Fig. 2. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on cold allodynia. Mean (±S.E.M.) withdrawal latencies to tail immersion in a cold (4 ◦ C) water bath are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes a withdrawal latency that is significantly different from N14 (P < 0.05).
S.K. Back et al. / Neuroscience Letters 368 (2004) 341–344
Fig. 3. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on warm allodynia. Mean (±S.E.M.) withdrawal latencies to tail immersion in a 40 ◦ C warm bath are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes values significantly different from N14 (P < 0.05).
demonstrated that mechanical allodynia was significantly attenuated by gabapentin in the spinal nerve ligation (SNL) model. In addition, Pan et al. [16] provided evidence that gabapentin suppressed mechanical allodynia in the partial nerve injury (PNI) model. Moreover, Xiao and Bennett [25] reported that gabapentin produced a significant suppression of mechanical allodynia and heat hyperalgesia in the chronic constriction injury (CCI) model. Taken together, these reports suggested that gabapentin preferentially attenuated mechanical and warm allodynia, and heat hyperalgesia. Unlike mechanical and warm allodynia, the analgesic effect of gabapentin on cold allodynia remained controversial. Our present findings of an analgesic effect of gabapentin on cold allodynia in the rat are consistent with the following recent results obtained in the rat CCI model; (1) gabapentin (100 mg/kg, i.p.) produced a dose-dependent increase in the latency to paw withdrawal from cold water (0 ◦ C) hindpaw immersion [9], (2) gabapentin (30 mg/kg, i.p.) increased the struggle latency to hindpaw immersion in a non-noxious cold water bath (10 ◦ C) [11], and (3) gabapentin (100 mg/kg, s.c.) blocked cold allodynia as manifested by normalization of the hindpaw withdrawal latency on a 5 ◦ C cold plate [23]. In contrast, the administration of gabapentin to rats in the spared nerve injury model [6], and photochemically induced ischemic peripheral nerve injury rat model [24], did not reduce the response frequency to cold stimulation by spraying ethyl chloride. While the reason for this disparity is unclear, it is possible that it may reflect a difference in the stimulated site: paw versus tail, stimulus type: paw/tail immersion versus cold spray or data acquisition methods, i.e., withdrawal latency versus response frequency. In fact, a dissociation of behaviors between the cold plate and the acetone spray tests was
343
demonstrated in the SNL model [4]. That is, some animals exhibited a high withdrawal response frequency to spraying acetone, but short duration of foot lifting off a cold plate, and vice versa. Alternatively, the different modes of nerve damage in these models may be another possible cause. To exclude the possibility that the antiallodynic effect of gabapentin in the present study reflected motor depression, a pinprick test was performed in intact animals. The tailwithdrawal responses, accompanied by vocalization, did not change after the injection of gabapentin. In line with the present results, gabapentin administration did not alter the tactile withdrawal threshold in intact animals [8]. Although individual neuropathic symptoms following peripheral nerve injury are induced by specific pathophysiological mechanisms, several symptoms may share common mechanisms. The observed antiallodynic effect of gabapentin may be related to its specific binding to the ␣ 2␦ subunit of the voltage-dependent Ca2+ channel. This subunit significantly upregulates in the dorsal root ganglia associated with nerve injury [13]. Thus, the effect of gabapentin may be mediated by a reduction in Ca2+ influx into neurons [22]. In addition, the fact that gabapentin suppressed ectopic discharge activity from injured peripheral nerve injury may contribute to the antiallodynic actions of gabapentin [16]. In summary, these results demonstrate that systemic administration of gabapentin relieves mechanical, warm and cold allodynia induced by peripheral nerve injury.
Acknowledgement This research was supported by a grant (M103KV01000903K220100910) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea.
References [1] S. Abdi, D.H. Lee, J.M. Chung, The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain, Anesth. Analg. 87 (1998) 1360–1366. [2] S. Arner, B.A. Meyerson, Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain, Pain 33 (1988) 11–23. [3] M. Backonja, A. Beydoun, K.R. Edward, S.L. Schwartz, V. Fonseca, M. Hes, L. LaMoreaux, E. Garofalo, Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial, J. Am. Med. Assoc. 280 (1998) 1831–1836. [4] Y. Choi, Y.W. Yoon, H.S. Na, S.H. Kim, J.M. Chung, Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain, Pain 59 (1994) 369–376. [5] M. Devor, Nerve pathophysiology and mechanisms of pain in causalgia, J. Auton. Nerv. Syst. 7 (1983) 371–384. [6] H.K. Erichsen, G. Blackburn-Munro, Pharmacological characterisation of the spared nerve injury model of neuropathic pain, Pain 98 (2002) 151–161. [7] A. Fox, C. Gentry, S. Patel, A. Kesingland, S. Bevan, Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine,
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S.K. Back et al. / Neuroscience Letters 368 (2004) 341–344 lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea pig, Pain 105 (2003) 355–362. H. Gustafsson, K. Flood, O.G. Berge, E. Brodin, L. Olgart, C.O. Stiller, Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice, Exp. Neurol. 182 (2003) 427–434. J.C. Hunter, K.R. Gogas, L.R. Hedley, L.O. Jacobson, L. Kassotakis, J. Thompson, D.J. Fontana, The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain, Eur. J. Pharmacol. 324 (1997) 153–160. J.H. Hwang, T.L. Yaksh, Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat, Reg. Anesth. 22 (1997) 249–256. V. Kayser, D. Christensen, Antinociceptive effect of systemic gabapentin in mononeuropathic rats depends on stimulus characteristics and level of test integration, Pain 88 (2000) 53–60. Y.I. Kim, H.S. Na, J.S. Han, S.K. Hong, Critical role of the capsaicin-sensitive nerve fibers in the development of the causalgic symptoms produced by transecting some but not all of the nerves innervating the rat tail, J. Neurosci. 15 (1995) 4133–4139. Z.D. Luo, S.R. Chaplan, E.S. Higuera, L.S. Sorkin, K.A. Stauderman, M.E. Williams, T.L. Yakshi, Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats, J. Neurosci. 21 (2001) 1868–1875. M.B. Max, S.C. Schafer, M. Culnane, R. Dubner, R.H. Gracely, Association of pain relief with drug side-effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo, Clin. Pharmacol. Ther. 43 (1988) 363–371. H. McQuary, D. Carroll, A.R. Jadad, D. Wiffen, A. Moore, Anticonvulsant drugs for the management of pain: a systematic review, Br. Med. J. 311 (1995) 1047–1052.
[16] H.L. Pan, J.C. Eisenach, S.R. Chen, Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats, J. Pharmacol. Exp. Ther. (1999) 288. [17] R.S. Richards, Causalgia, Arch. Neurol. 16 (1967) 339–350. [18] M.A. Rose, P.C. Kam, Gabapentin: pharmacology and its use in pain management, Anaesthesia 57 (2002) 451–462. [19] H. Rosner, L. Rubin, A. Kestenbaum, Gabapentin adjunctive therapy in neuropathic pain states, Clin. J. Pain. 12 (1996) 56–58. [20] B. Sung, H.S. Na, Y.I. Kim, Y.W. Yoon, H.C. Han, S.H. Nahm, S.K. Hong, Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats, Neurosci. Lett. 246 (1998) 117–119. [21] A.J. Tahmoush, Causalgia: redefinition as a clinical pain syndrome, Pain 10 (1981) 187–197. [22] C.P. Taylor, N.S. Gee, T.Z. Su, J.D. Kocsis, D.F. Welty, J.P. Brown, D.J. Dooley, P. Boden, L. Singh, A summary of mechanistic hypotheses of gabapentin pharmacology, Epilepsy Res. 29 (1998) 231– 249. [23] G. Villetti, M. Bergamaschi, F. Bassani, P.T. Bolzoni, M. Maiorino, C. Pietra, I. Rondelli, P. Chamiot-Clerc, M. Simonato, M. Barbieri, Antinociceptive activity of the N-methyl-d-aspartate receptor antagonist N-(2-indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain, J. Pharmacol. Exp. Ther. 306 (2003) 804–814. [24] W.P. Wu, J.X. Hao, E. Ongini, F. Impagnatiello, C. Presotto, Z. Wiesenfeld-Hallin, X.J. Xu, A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury, Br. J. Pharmacol. 141 (2004) 65–74. [25] W.H. Xiao, G.J. Bennett, Gabapentin relieves abnormal pains in a rat model of painful peripheral neuropathy, Soc. Neurosci. Abstr. 21 (1995) 897.
Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy Seung Keun Back, Sang Youn Won, Seung Kil Hong, Heung Sik Na∗ Department of Physiology, Medical Science Research Center, Korea University College of Medicine, 126-1 Anam-dong 5 Ga, Sungbuk-Gu, Seoul 136-705, Korea Received 24 May 2004; received in revised form 30 July 2004; accepted 31 July 2004
Abstract Although recent studies demonstrated the relieving effect of gabapentin on neuropathic pain, the effect has not been sufficiently examined. In the present study, we investigated the effect of gabapentin on mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Under enflurane anesthesia, animals were subjected to the partial injury of the nerves innervating the tail. Behavioral tests for mechanical, cold and warm allodynia on the tail were performed by von Frey hair (2.0 g) stimulation, 4 and 40 ◦ C water immersion, respectively. Intraperitoneal injection of gabapentin (30, 100, 300 mg/kg) significantly alleviated mechanical, warm and cold allodynia in a dose-dependent manner. Our results suggest that gabapentin is an effective agent against mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Neuropathic pain; Gabapentin; Peripheral neuropathy; Allodynia
Peripheral nerve injury often results in chronic neuropathic pain syndromes such as spontaneous burning pain, hyperalgesia and allodynia [5,17,21]. Neuropathic pains are often poorly treated by currently available medications; opioids [2] and non-steroidal anti-inflammatory drugs [14]. Recently, anticonvulsant gabapentin is widely becoming accepted as an alternative therapeutic agent for neuropathic pain [18]. However, despite the possibility that individual neuropathic signs resulting from particular pathomechanisms may require different management strategies, the effect of gabapentin against neuropathic pain has not been extensively examined. In addition, although gabapentin has significantly alleviated mechanical allodynia and heat hyperalgesia in neuropathic animals [1,7] as well as in patients with neuropathy [3,15,19], the analgesic effect on cold allodynia remains controversial [6,9,11,23,24]. In the present study, we investigated the effect of gabapentin on mechanical, warm and cold of allodynia in a rat model of peripheral neuropathy. As far as we know, ∗ Corresponding author. Tel.: +82 2 920 6188; fax: +82 2 925 5492. E-mail address: [email protected] (H.S. Na).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.07.091
this is the first report on the simultaneous examination of the analgesic effect of gabapentin on mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Young adult male Sprague–Dawley rats (150–200 g, n = 60) were used in this study. The neuropathic surgery was based on the procedure previously described by Sung et al. [20]. In brief, under enflurane anesthesia (0.5–2.0%) animals were subjected to the unilateral transection of the superior caudal trunk at the level between the S3 and S4 spinal nerve. This surgery partially injured the S1–S3 spinal nerves innervating the tail. To monitor the generation of neuropathic pain, the behavioral tests for mechanical, cold and warm allodynia were carried out in all experimental animals 1 day prior to and 1, 7 and 14 day(s) after nerve injury. As reported previously [12], mechanical allodynia was assessed by the tail-withdrawal response following poking the tail with a von Frey hair (bending force 2.0 g). The most sensitive spot of the tail was first determined by rubbing or poking various areas of the tail systematically with the von Frey hair. Then, this spot was challenged 10 times with 5–10 s intervals with the von Frey hair. The occurrence of tail withdrawal, in response to the
342
S.K. Back et al. / Neuroscience Letters 368 (2004) 341–344
indentation of the rat tail skin with the hair, was expressed as a percentage of trials. The tests for cold and warm allodynia were performed by immersing the tail into cold (4 ◦ C) or warm (40 ◦ C) water, respectively, measuring the latency of tail withdrawal or twitch, within a cut-off time of 15 s. The tests for cold and warm allodynia were repeated five times with 5 min intervals. The average latency of tail response was calculated. After behavioral tests on post-surgery day 14, gabapentin (30, 100 or 300 mg/kg, Sigma, St. Louis, MO, USA) or saline vehicle were administered intraperitoneally. Thereafter, behavioral tests for mechanical, cold and warm allodynia were performed at 1, 3, 5 h and 1, 2 days after the injection. We also examined if a noxious pinprick applied to the tail could evoke a tail-withdrawal response after gabapentin injection in intact animals (n = 5), without peripheral nerve injury. The pinprick test was repeated 10 times at a 10–20 s interval to determine the response frequency. Behavioral data of the present study were obtained in a blind fashion; the investigators who conducted behavioral experiments were unaware of the injection status of the rats, and those who performed the injection were unaware of the behavioral results. Data are expressed as mean ± S.E.M. Statistical analysis was conducted with the Friedman repeated measures ANOVA followed by a pairwise comparison of pain behaviors between pre- and post-injection, utilizing a Dunnett’s t-test on the ranked data. P < 0.05 was considered to be significant. Before nerve injury, animals rarely exhibited tailwithdrawal responses to von Frey hair, cold (4 ◦ C) and warm (40 ◦ C) water stimuli (Figs. 1–3). However, post-operative animals showed significantly increased tail-withdrawal frequency to von Frey hair stimulation (P < 0.05) and markedly decreased tail-withdrawal latencies to cold or warm water stimuli (P < 0.05, respectively). These sensory abnormalities are widely accepted as signs of mechanical, cold and warm allodynia. Figs. 1–3 illustrate that gabapentin administered intraperitoneally on post-surgery day 14 significantly alleviated the mechanical, warm and cold allodynia, respectively, in a dosedependent manner, with a maximal effect between 1 and 3 h after the injection (P < 0.05, Dunnett’s t-test). The highest dose of gabapentin (300 mg/kg) completely alleviated the mechanical and warm allodynia, and this antiallodynic effect lasted for a day after the injection. However, cold allodynia was less sensitive to gabapentin than mechanical and warm allodynia (Figs. 1–3). No effect on the allodynia was observed in animals injected with the saline vehicle. In order to test for normal reflex behavior in the presence of drug, a noxious mechanical (pinprick) stimulus was applied to the tail skin of normal animal. The pinprick induced a tailwithdrawal response, accompanied by vocalization in >90% of the trials even 1 h after the injection of the highest dose (300 mg/kg, data not shown). The present results show that gabapentin significantly alleviated in rat the mechanical, warm and cold of allodynia in
Fig. 1. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on mechanical allodynia. Mean (±S.E.M.) response frequencies to 10 applications of a von Frey hair (19.6 mN, 2.0 g) on the tail skin are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes a response frequency that is significantly different from N14 (P < 0.05).
a dose-dependent manner, with a maximal effect between 1 and 3 h after the injection. In line with the present results, previous studies demonstrated that gabapentin significantly attenuates neuropathic pain behavior in several animal models of peripheral neuropathy. Hwang and Yaksh [10], and Abdi et al. [1]
Fig. 2. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on cold allodynia. Mean (±S.E.M.) withdrawal latencies to tail immersion in a cold (4 ◦ C) water bath are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes a withdrawal latency that is significantly different from N14 (P < 0.05).
S.K. Back et al. / Neuroscience Letters 368 (2004) 341–344
Fig. 3. Antiallodynic effect of intraperitoneally injected gabapentin (GBP) on warm allodynia. Mean (±S.E.M.) withdrawal latencies to tail immersion in a 40 ◦ C warm bath are plotted against post-operative times: ‘P’, preoperative day; ‘d’, day(s) after nerve injury; ‘h’, hour(s) after the injection of gabapentin. The dashed line indicates the time of injection. Asterisk (*) denotes values significantly different from N14 (P < 0.05).
demonstrated that mechanical allodynia was significantly attenuated by gabapentin in the spinal nerve ligation (SNL) model. In addition, Pan et al. [16] provided evidence that gabapentin suppressed mechanical allodynia in the partial nerve injury (PNI) model. Moreover, Xiao and Bennett [25] reported that gabapentin produced a significant suppression of mechanical allodynia and heat hyperalgesia in the chronic constriction injury (CCI) model. Taken together, these reports suggested that gabapentin preferentially attenuated mechanical and warm allodynia, and heat hyperalgesia. Unlike mechanical and warm allodynia, the analgesic effect of gabapentin on cold allodynia remained controversial. Our present findings of an analgesic effect of gabapentin on cold allodynia in the rat are consistent with the following recent results obtained in the rat CCI model; (1) gabapentin (100 mg/kg, i.p.) produced a dose-dependent increase in the latency to paw withdrawal from cold water (0 ◦ C) hindpaw immersion [9], (2) gabapentin (30 mg/kg, i.p.) increased the struggle latency to hindpaw immersion in a non-noxious cold water bath (10 ◦ C) [11], and (3) gabapentin (100 mg/kg, s.c.) blocked cold allodynia as manifested by normalization of the hindpaw withdrawal latency on a 5 ◦ C cold plate [23]. In contrast, the administration of gabapentin to rats in the spared nerve injury model [6], and photochemically induced ischemic peripheral nerve injury rat model [24], did not reduce the response frequency to cold stimulation by spraying ethyl chloride. While the reason for this disparity is unclear, it is possible that it may reflect a difference in the stimulated site: paw versus tail, stimulus type: paw/tail immersion versus cold spray or data acquisition methods, i.e., withdrawal latency versus response frequency. In fact, a dissociation of behaviors between the cold plate and the acetone spray tests was
343
demonstrated in the SNL model [4]. That is, some animals exhibited a high withdrawal response frequency to spraying acetone, but short duration of foot lifting off a cold plate, and vice versa. Alternatively, the different modes of nerve damage in these models may be another possible cause. To exclude the possibility that the antiallodynic effect of gabapentin in the present study reflected motor depression, a pinprick test was performed in intact animals. The tailwithdrawal responses, accompanied by vocalization, did not change after the injection of gabapentin. In line with the present results, gabapentin administration did not alter the tactile withdrawal threshold in intact animals [8]. Although individual neuropathic symptoms following peripheral nerve injury are induced by specific pathophysiological mechanisms, several symptoms may share common mechanisms. The observed antiallodynic effect of gabapentin may be related to its specific binding to the ␣ 2␦ subunit of the voltage-dependent Ca2+ channel. This subunit significantly upregulates in the dorsal root ganglia associated with nerve injury [13]. Thus, the effect of gabapentin may be mediated by a reduction in Ca2+ influx into neurons [22]. In addition, the fact that gabapentin suppressed ectopic discharge activity from injured peripheral nerve injury may contribute to the antiallodynic actions of gabapentin [16]. In summary, these results demonstrate that systemic administration of gabapentin relieves mechanical, warm and cold allodynia induced by peripheral nerve injury.
Acknowledgement This research was supported by a grant (M103KV01000903K220100910) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea.
References [1] S. Abdi, D.H. Lee, J.M. Chung, The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain, Anesth. Analg. 87 (1998) 1360–1366. [2] S. Arner, B.A. Meyerson, Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain, Pain 33 (1988) 11–23. [3] M. Backonja, A. Beydoun, K.R. Edward, S.L. Schwartz, V. Fonseca, M. Hes, L. LaMoreaux, E. Garofalo, Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial, J. Am. Med. Assoc. 280 (1998) 1831–1836. [4] Y. Choi, Y.W. Yoon, H.S. Na, S.H. Kim, J.M. Chung, Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain, Pain 59 (1994) 369–376. [5] M. Devor, Nerve pathophysiology and mechanisms of pain in causalgia, J. Auton. Nerv. Syst. 7 (1983) 371–384. [6] H.K. Erichsen, G. Blackburn-Munro, Pharmacological characterisation of the spared nerve injury model of neuropathic pain, Pain 98 (2002) 151–161. [7] A. Fox, C. Gentry, S. Patel, A. Kesingland, S. Bevan, Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine,
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