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Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the l -arginine–NO pathway and opioid system
Life Sciences 78 (2006) 1592 – 1597 www.elsevier.com/locate/lifescie
Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the l-arginine–NO pathway and opioid system Ahmet Ulugol *, Dikmen Dokmeci, Gurkan Guray, Nese Sapolyo, Filiz Ozyigit, Melek Tamer Department of Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey Received 16 February 2005; accepted 21 July 2005
Abstract The present study was undertaken to determine the effects of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) melatonin on mechanical allodynia and thermal hyperalgesia in mice with partial tight ligation of the sciatic nerve, and how the nitric oxide (NO) precursor l-arginine and the opiate antagonist naloxone influence this effect. A plantar analgesic meter was used to assess thermal hyperalgesia, and nerve injury-induced mechanical hyperalgesia was assessed with von Frey filaments. 1 – 5 weeks following the surgery, marked mechanical allodynia and thermal hyperalgesia developed in neuropathic mice. Intracerebroventricular and intraperitoneal melatonin, with its higher doses, produced a blockade of thermal hyperalgesia, but not mechanical allodynia. Administration of both l-arginine and naloxone, at doses which produced no effect on their own, partially reversed antihyperalgesic effect of melatonin. These results suggest that although it has different effects on neuropathic pain-related behaviors, melatonin may have clinical utility in neuropathic pain therapy in the future. It is also concluded that l-arginine – NO pathway and opioidergic system are involved in the antihyperalgesic effect of melatonin in nerve-injured mice. D 2005 Elsevier Inc. All rights reserved. Keywords: Neuropathic pain; Allodynia; Hyperalgesia; Melatonin
Introduction Nerve injury that affects peripheral nerves leads to abnormal pain conditions referred to as neuropathic pain. Mechanical allodynia (nociceptive responses to normally innocuous stimuli) and thermal hyperalgesia (augmented pain intensity in response to normally painful stimuli) are two frequently seen clinical symptoms associated with neuropathic pain. Several animal models have recently been developed to investigate the mechanisms underlying this chronic pain state (Bennett and Xie, 1988; Kim and Chung, 1992; Seltzer et al., 1990). Most of these models have been developed in the rat; however, there is a need to adapt the rat models to the mouse to define the molecular basis and mechanisms of neuropathic pain. Partial tight ligation of the sciatic nerve in rats is a widely employed model, which produces spontaneous pain, allodynia and hyperalgesia, analogous to clinical conditions of neuropathic pain (Seltzer et al., * Corresponding author. Tel.: +90 532 4316449; fax: +90 284 2353925. E-mail address: [email protected] (A. Ulugol). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.07.002
1990; Seltzer, 1995); recently the same model has also been applied in mice (Malmberg and Basbaum, 1998). Neuropathic pain is generally accepted to be particularly insensitive to drug treatment, including the potent analgesics, opioids (Benedetti et al., 1998; MacFarlane et al., 1997; Watson, 2000). Tricyclic antidepressants and gabapentin are often prescribed, with variable responses and effectiveness (MacFarlane et al., 1997). Although considerable efforts have been spent on the discovery of novel analgesics for the treatment of chronic pain syndromes, there is not much improvement observed, and there seems to be an urgent need for effective drugs in these cases. Melatonin (N-acetyl-5-methoxytryptamine) is known as a neurohormone that is synthesized and secreted mainly by the pineal gland from the amino acid precursor l-tryptophan. Although the physiological significance of melatonin is not yet fully understood, the involvement in circadian rhythms is the best described function of the hormone (Pacchierotti et al., 2001). Melatonin has also been shown to be involved in some psychopharmacological effects including the sedative/hypnotic,
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anticonvulsant and anti-anxiety effects (Geoffriau et al., 1998; Golombek et al., 1996; Sugden, 1983). N-methyl-d-aspartate (NMDA) receptors and the l-arginine –NO pathway, opioidergic and GABAergic systems have been shown to play a role in these behavioral effects of melatonin (Golombek et al., 1991, 1996; Mantovani et al., 2003). Moreover, a number of reports indicate that the hormone exerts a potent and long-lasting antinociceptive effect (Golombek et al., 1991; Lakin et al., 1981; Sugden, 1983; Yu et al., 1999, 2000b). However, no report so far has addressed the modulation of neuropathic pain behaviors, such as allodynia and hyperalgesia, by melatonin. Therefore, the aim of this study was, firstly, to determine whether melatonin affects mechanical allodynia and thermal hyperalgesia in sciatic nerve-ligated neuropathic mice and, secondly, to analyze to what extent the activity of melatonin can be inhibited by the NO precursor l-arginine and the opiate antagonist naloxone.
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min before starting the experiments. To minimize the differences in technique, the same person performed each operation. Assessment of mechanical allodynia Mechanical allodynia thresholds were assessed, as described previously (Hao et al., 2000; Gustafsson et al., 2003). Briefly, eight von Frey filaments, with approximately equal logarithmic incremental bending forces, were chosen (von Frey numbers: 2.44, 2.83, 3.22, 3.61, 4.08, 4.31, 4.56, 4.93; equivalent to 0.04, 0.07, 0.16, 0.4, 1, 2, 4, 8 g, respectively). Each hair was pressed perpendicularly against the paw until slight buckling was observed. The area tested was the middle area between the footpads of the plantar surface of the hindpaw. Testing was initiated with the 0.04 g hair and kept on in an ascending order of force. The withdrawal threshold was defined as the force at which the mouse withdrew the paw from at least three of the five consecutive applications.
Materials and methods Assessment of thermal hyperalgesia This study was conducted according to the guidelines of the Ethical Committee of the International Association for the Study of Pain (Zimmermann, 1983), and had been approved by the ‘‘Animal Care Ethics Committee’’ of our faculty. Animals Male bulb-c albino mice (Center of the Laboratory Animals, Eczacibasi-Turkey), weighing 20 –25 g at time of operation, were used for the experiments. The mice were housed ten in a cage in a quiet room and had free access to standard laboratory food and tap water. The ambient temperature was kept at 22 T 1 -C, since lowering ambient temperature has been shown to augment abnormalities in pain-related behaviors of neuropathic pain (Sato et al., 2000). Surgery Under ketamine/xylazine anesthesia (100 mg/kg/10 mg/kg, i.p.), a partial nerve ligation of the sciatic nerve was made by tightly tying 1/3 to 1/2 of the dorsal portion of the sciatic nerve, using a similar procedure to that described for rats by Seltzer et al. (1990) and for mice by Malmberg and Basbaum (1998). In shamoperated mice the nerve was exposed, but not ligated. After confirming a complete hemostasis, the muscle and the skin was sutured and the mice were returned to their cages after full recovery from anesthesia. Mice with this nerve injury have been shown to develop mechanical and thermal allodynia and hyperalgesia and are used as a model for neuropathic pain (Bortalanza et al., 2002; Malmberg and Basbaum, 1998; Shields et al., 2003). Behavioral testing The mice were placed under a glass cover on a metal mesh floor for assessments of tactile allodynia and in a plexiglass box of a Plantar test apparatus for assessments of mechanical hyperalgesia, and adapted to testing environment for at least 15
Thermal nociceptive threshold to radiant heat was quantified using the method of Hargreaves et al. (1988). Briefly, mice were placed in a plexiglass box on top of the temperature maintained (30 T 0.1 -C) glass surface of the stimulator (Maycom, Turkey). A beam of radiant heat was applied through the glass to the plantar surface of the hind paw. The paw withdrawal latency, defined as the time from onset of the radiant heat to the withdrawal of the paw, was detected with a photocell and a timer. The radiant heat source was adjusted to result in pre-injection latencies of 12– 13 s. A maximal cut-off of 20 s was used to prevent tissue damage. Experimental design Tests took place 2 – 3 weeks after tight ligation of the sciatic nerve. Mechanical allodynia and thermal hyperalgesia thresholds were assessed immediately before, and at 0.5, 1, and 2 h after drug injections. After testing different doses of intraperitoneal (30, 60, 120 mg/kg, i.p.) and intracerebroventricular (0.001, 0.01, 0.1 nmol, i.c.v.) melatonin, concomitant administrations of l-arginine (200 mg/kg, i.p.; 80 Ag, i.c.v.) and naloxone (1 mg/kg, i.p.; 10 Ag, i.c.v.) with the effective doses of melatonin (120 mg/kg, i.p.; 0.1 nmol, i.c.v.) was investigated. The effectiveness of l-arginine and naloxone on mechanical allodynia and thermal hyperalgesia, when administered alone, were also evaluated. Drugs Melatonin and l-arginine were obtained from Sigma Chemical Co., while naloxone was purchased from Research Biochemicals Inc. All chemicals were dissolved in isotonic NaCl, and i.p. administrations were made in a volume of 0.1 ml/100 g body weight. For i.c.v. administration, the drugs were injected in the necessary dosage, in a volume of 5 Al/mouse using a Hamilton’s microlitre syringe following the method of
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Fig. 1. Changes in withdrawal latency to thermal stimulation (A) and in withdrawal threshold to mechanical stimulation with von Frey hairs (B) in sciatic nerveligated and sham-operated mice. Withdrawal thresholds and latencies were assessed before (Pre) and 1 – 5 weeks after the operation. (*P < 0.05, compared to corresponding values in the control group; ANOVA followed by Newman – Keuls test).
Haley and McCormick (1957). The reliability of the method was confirmed by pilot studies using injection of India ink and macroscopically observing its diffusion into various parts of the brain after sectioning. The site of injection was 1.5 mm from either side of the midline on a line drawn through the anterior base of the ears. After grasping the head of the mouse firmly, the needle of the 10 Al Hamilton syringe was inserted perpendicularly 3 mm through the skull into the brain. Then, the solution was injected slowly, in 20 s, into the right lateral ventricle. For either i.p. or i.c.v. administrations, the equivalent volume of vehicle was administered to the control groups. Statistical analysis Data were analyzed by analysis of variance (ANOVA) followed by Newman – Keuls test. Values of P < 0.05 were considered to be significant. All data are expressed as mean T SEM. Results Effects of tight ligation of the sciatic nerve As described previously (Bortalanza et al., 2002; Malmberg and Basbaum, 1998; Shields et al., 2003), mice subjected to tight
ligation of the sciatic nerve developed pain-related behavior, marked as mechanical allodynia and thermal hyperalgesia. Withdrawal threshold (assessing mechanical allodynia) and withdrawal latencies (assessing thermal hyperalgesia) during the 5-week period after the surgery are shown in Fig. 1A,B. Prior to operation, mice rarely responded to thinner von Frey hairs and were slower when withdrawing their hind paws from the radiant heat beam; paw withdrawal threshold for mechanical allodynia and withdrawal latency for thermal hyperalgesia being 1.7 T 0.1 and 13.1 T1.2, respectively (Fig. 1A,B). One to five weeks after nerve injury, significant reduction both in paw withdrawal thresholds to von Frey filaments and in withdrawal latencies to radiant heat were observed (Fig. 1A,B). Effects of i.p. and i.c.v. melatonin on mechanical allodynia and thermal hyperalgesia With its highest doses, both i.p. (120 mg/kg) and i.c.v. (0.1 nmol) administrations of melatonin reduced paw withdrawal latencies in response to radiant heat stimulation of the injured hindpaw, compared to corresponding values in the control group ( p < 0.05, Fig. 2A,B). No significant drug effect was observed 2 h post drug administrations (Fig. 2A,B). In the case of mechanical allodynia, neither i.p. nor i.c.v. melatonin had any effect on the withdrawal thresholds to von Frey hairs,
Fig. 2. Effects of i.c.v. (A) i.p. (B) injections of vehicle (n = 6) and three doses of melatonin (0.001 – 0.1 nmol, i.c.v; 30 – 120 mg/kg, i.p.; n = 6 for each dose) on thermal hyperalgesia. Preoperative (Pre) values were determined before the operation. Withdrawal latencies were also assessed before (0) and 0.5, 1, and 2 h after drug administrations. (*P < 0.05, compared to corresponding values in the control group; ANOVA followed by Newman – Keuls test).
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Fig. 3. Antihyperalgesic effect of i.c.v. (A) and i.p. (B) melatonin (Mel, 0.1 nmol, i.c.v.; 120 mg/kg, i.p.), and prevention of this effect by l-arginine (l-arg, 80 Ag, i.c.v.; 200 mg/kg, i.p.) and naloxone (Nal, 10 Ag, i.c.v.; 1 mg/kg, i.p.). Withdrawal latencies were assessed 0.5, 1, and 2 h after drug administrations. n = 6 – 7 per group. (*P < 0.05, compared to corresponding values in the control group; +P < 0.05, compared to corresponding values in the combination group; ANOVA followed by Newman – Keuls test).
compared to the respective pre-injection baseline value. No signs of side effects such as sedation or motor impairment were noted following either the surgery or the melatonin administrations at any dose. Effects of l -arginine and naloxone on melatonin administration Concomitant administrations of both l-arginine (200 mg/kg, i.p.; 80 Ag, i.c.v.) and naloxone (1 mg/kg, i.p.; 10 Ag, i.c.v.), at doses which produced no effect on their own when administered either i.p. or i.c.v., reduced the effect of melatonin (120 mg/kg, i.p.; 0.1 nmol, i.c.v.) on thermal hyperalgesia (Fig. 3A,B). Their influence on the effect of melatonin on mechanical allodynia is not determined, since melatonin did not affect this neuropathic pain behavior. Discussion Neuropathic pain is very difficult to manage clinically. Tricyclic antidepressants and anticonvulsant drugs are often prescribed, but both are associated with significant use-limiting adverse effects (MacFarlane et al., 1997; Watson, 2000; Woolf and Mannion, 1999). The potent analgesics, opioids, on the other hand, are effective only in some conditions of neuropathic pain, such as postherpetic neuralgia and diabetic neuropathy. Most of the other chronic pain conditions are still considered to be relatively insensitive to opioid treatment (Benedetti et al., 1998; MacFarlane et al., 1997; Watson, 2000), suggesting the need for new effective drugs in neuropathic states. In addition to new effective drugs, new mouse models will also be necessary both to perform genetic studies readily and to explore the molecular basis and mechanisms of neuropathic pain. Mice used in our study exerted significant mechanical allodynia and thermal hyperalgesia after the surgery. Although Shields et al. (2003) did not observe thermal hyperalgesia after similar operation; our results are consistent with those of Malmberg and Basbaum (1998). There are few reports indicating hyperalgesic or no effect of melatonin on analgesia (Psarakis et al., 1988; Takahashi et al.,
1987), and attenuation of morphine analgesia by melatonin (Datta et al., 1982). Conversely, accumulating evidence indicates that melatonin has a potent and long-lasting antinociceptive activity (Golombek et al., 1991, 1996; Lakin et al., 1981; Sugden, 1983; Yu et al., 1999, 2000b). Apart from its known efficacy on acute pain states, the effects of melatonin on behavioral signs of neuropathic pain, such as allodynia and hyperalgesia, have not been studied. Sugden has reported that melatonin had very low acute toxicity when administered to mice and rats by various routes (1983). Taken together, melatonin seems to be a promising drug for the treatment of neuropathic pain. Our findings support this suggestion, since we also did not observe any signs of side effects such as sedation or motor impairment at any dose of melatonin, and showed for the first time the effectiveness of melatonin in a chronic pain condition. Several effects of melatonin, including analgesia, are known to be time-dependent. Although melatonin has been shown to exhibit maximal analgesic effects at the light– dark transitional period (Golombek et al., 1991, 1996), there are reports indicating that it is also efficacious at the mid-light period, but with its pharmacological doses (Golombek et al., 1991; Lakin et al., 1981; Sugden, 1983). Melatonin augmentation of morphine induced analgesia in the daytime has also been reported (Kavaliers et al., 1983). These reports are in line with our findings, since we observed the anti-hyperalgesic effect of melatonin during the mid-light period, only with its higher doses tested. Despite intensive investigation, the precise effects of larginine –NO – cGMP pathway on acute and chronic pain states remain unclear. There are observations indicating that larginine –NO – cGMP pathway exerts a hyperalgesic action; however, it is generally believed that it has an antinociceptive effect (Meller et al., 1992; Moore et al., 1991). It has also been shown that NO mediates behavioral signs of neuropathic pain (Yoon et al., 1998), and that NG-nitro-l-arginine-methyl ester (L-NAME), a NO synthase inhibitor, inhibited mechanical and cold allodynia in neuropathic rats (Ulugol et al., 2002). Moreover, morphine has been shown to induce antinociception by the activation of the l-arginine – NO – cGMP pathway
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(Granados-Soto et al., 1997). Recently, it has been indicated that melatonin exerts an antidepressant-like effect in the mouse tail suspension test, which seems to be mediated through an interaction with NMDA receptors and l-arginine –NO pathway (Mantovani et al., 2003). Taken together, although it is generally assumed that melatonin exerts responses through activation of melatonin receptors (Yu et al., 2000b); one might expect l-arginine –NO – cGMP pathway to play a role in melatonin analgesia. Opioidergic and GABAergic systems have also been shown to play a role in the behavioral effects of melatonin (Golombek et al., 1991, 1996; Mantovani et al., 2003). Opioid or central-type benzodiazepine antagonism has been shown to inhibit melatonin analgesia, and GABAergic system has been shown to play a role in the inhibitory (sedation, hypnotic activity, antinociceptive, anticonvulsive, anti-anxiety effects) effects of melatonin (Golombek et al., 1991, 1996). It has also been suggested that melatonin promotes the release of h-endorphin in the brain, which may be one of the mechanisms of action of melatonin to induce analgesia (Yu et al., 2000a). Similar to these results, we observed that concomitant administrations of both l-arginine and naloxone reduce the effect of melatonin on thermal hyperalgesia, indicating the role of l-arginine – NO pathway and opioidergic system in the anti-hyperalgesic effect of melatonin. Mechanical allodynia and thermal hyperalgesia, two principal manifestations of neuropathic pain, are suggested to be mediated through separate mechanisms and neuronal pathways; the exact mechanisms underlying these behavioral signs of neuropathic pain remain poorly understood and the drugs may affect these manifestations conversely. Morphine, for example, has been shown to block small (C and Ay) but not large diameter (Ah) fibre evoked responses into the dorsal horn (Dickenson and Sullivan, 1986; Le Bars et al., 1979). Tactile allodynia has been suggested to be mediated through large diameter, Ah-afferent fibers, whereas thermal hyperalgesia is likely to be mediated through small diameter, unmyelinated high threshold C-fibers (Ossipov et al., 1999; Shir and Seltzer, 1998). Accordingly, thermal hyperalgesia has been shown to be more sensitive to morphine administration than dynamic allodynia, and the failure of morphine to block dynamic allodynia suggests that it is mediated by Ah-fibers (Field et al., 1999; Sun et al., 2001). Taken together, mechanical allodynia seems to be much more difficult to manage; our findings are also in line with this suggestion, since melatonin exerted antihyperalgesic, but not antiallodynic effect. Conclusion As a result, our findings show that both i.c.v. and i.p. melatonin, with its higher doses, block thermal hyperalgesia, but not mechanical allodynia in neuropathic mice, and may be useful for the clinical management of chronic painful situations. Melatonin effect on thermal hyperalgesia is mediated, at least partially, by l-arginine – NO pathway and opioidergic system.
Acknowledgement The authors wish to thank Eczacibasi-Turkey for the mice. References Benedetti, F., Vighetti, S., Amanzio, M., Casadio, C., Oliaro, A., Bergamasco, B., Maggi, G., 1998. Dose – response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 74, 205 – 211. Bennett, G.J., Xie, Y.K., 1988. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87 – 107. Bortalanza, L., Ferreira, J., Hess, S.C., Monache, F.D., Yunes, R.A., Calixto, J.B., 2002. Anti-allodynic action of the tormentic acid, a triterpene isolated from plant, against neuropathic and inflammatory persistent pain in mice. European Journal of Pharmacology 453, 203 – 208. Datta, P.C., Sandman, C.A., Hoehler, F.K., 1982. Attenuation of morphine analgesia by (-MSH, MIF-I, melatonin and naloxone in the rat. Peptides 3, 433 – 437. Dickenson, A.H., Sullivan, A.F., 1986. Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurons in the rat dorsal horn. Pain 24, 211 – 222. Field, M.J., Bramwell, S., Hughes, J., Singh, L., 1999. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signaled by distinct primary sensory neurons? Pain 83, 303 – 311. Geoffriau, M., Brun, J., Chazot, G., Claustrat, B., 1998. The physiology and pharmacology of melatonin in humans. Hormone Research 49, 136 – 141. Golombek, D.A., Escolar, E., Burin, L.J., De-Brito-Sanchez, M.G., Cardinali, D.P., 1991. Time-dependent melatonin analgesia in mice: inhibition by opiate or benzodiazepine antagonism. European Journal of Pharmacology 194, 25 – 30. Golombek, D.A., Pevet, P., Cardinali, D.P., 1996. Melatonin effects on behavior: possible mediation by the central GABAergic system. Neuroscience and Biobehavioral Reviews 20, 403 – 412. Granados-Soto, V., Rufino, M.O., Lopes, L.D.G., Ferreira, S.H., 1997. Evidence for the involvement of the nitric oxide – cGMP pathway in the antinociception of morphine in the formalin test. European Journal of Pharmacology 340, 177 – 180. Gustafsson, H., Flood, K., Berge, O.G., Brodin, E., Olgart, L., Stiller, C.O., 2003. Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Experimental Neurology 182, 427 – 434. Haley, T.J., McCormick, W.G., 1957. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. British Journal of Pharmacology 12, 12 – 15. Hao, J.X., Blakeman, K.H., Yu, W., Hultenby, K., Xu, X.J., Wiesenfeld-Hallin, Z., 2000. Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve. Experimental Neurology 163, 231 – 238. Hargreaves, K., Dubner, R., Brown, F., Flores, C., Joris, J., 1988. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77 – 88. Kavaliers, M., Hirst, M., Teskey, G.C., 1983. Ageing, opioid analgesia and the pineal gland. Life Sciences 32, 2279 – 2287. Kim, S.H., Chung, J.M., 1992. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355 – 363. Lakin, M.L., Miller, C.H., Stott, M.L., Winters, W.D., 1981. Involvement of the pineal gland and melatonin in murine analgesia. Life Sciences 29, 2543 – 2551. Le Bars, D., Rivot, J.P., Guilbaud, G., Menetrey, D., Besson, J.M., 1979. The depressive effect of morphine on the C-fibre response of dorsal horn neurons in the spinal rat pretreated or not by pCPA. Brain Research 176, 337 – 353. MacFarlane, B.V., Wright, A., O’Callaghan, J., Benson, H.A.E., 1997. Chronic neuropathic pain and its control by drugs. Pharmacology & Therapeutics 75, 1 – 19.
A. Ulugol et al. / Life Sciences 78 (2006) 1592 – 1597 Malmberg, A.B., Basbaum, A.I., 1998. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76, 215 – 222. Mantovani, M., Pertile, R., Calixto, J.B., Santos, A.R.S., Rodrigues, A.L.S., 2003. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-Daspartate receptors and the L-arginine-nitric oxide pathway. Neuroscience Letters 343, 1 – 4. Meller, S.T., Pechman, P.S., Gebhart, G.F., Maves, T.J., 1992. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 50, 7 – 10. Moore, P.K., Oluyomi, A.O., Babbedge, R.C., Wallace, P., Hart, S.L., 1991. LNG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. British Journal of Pharmacology 102, 198 – 202. Ossipov, M.H., Bian, D., Malan Jr., T.P., Lai, J., Porreca, F., 1999. Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats. Pain 79, 127 – 133. Pacchierotti, C., Lapichino, S., Bossini, L., Pieraccini, F., Castrogiovanni, P., 2001. Melatonin in psychiatry disorders: a review on the melatonin involvement in psychiatry. Frontiers in Neuroendocrinology 22, 18 – 32. Psarakis, S., Brown, G.M., Grota, L.J., 1988. Analgesia induced by N-acetylserotonin in the central nervous system. Life Sciences 42, 1109 – 1116. Sato, J., Morimae, H., Takanari, K., Seino, Y., Okada, T., Suzuki, M., Mizumura, K., 2000. Effects of lowering ambient temperature on painrelated behaviors in a rat model of neuropathic pain. Experimental Brain Research 133, 442 – 449. Seltzer, Z., 1995. The relevance of animal neuropathy models for chronic pain in humans. Neurosciences 7, 211 – 219. Seltzer, Z., Dubner, R., Shir, Y., 1990. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205 – 218. Shields, S., Eckert, W.A., Basbaum, A.I., 2003. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. The Journal of Pain 4, 465 – 470.
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Shir, Y., Seltzer, Z., 1998. A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neuroscience Letters 115, 62 – 67. Sugden, D., 1983. Psychopharmacological effects of melatonin in mouse and rat. The Journal of Pharmacology and Experimental Therapeutics 227, 587 – 591. Sun, H., Ren, K., Zhong, C.M., Ossipov, M.H., Malan Jr., T.P., Lai, J., Porreca, F., 2001. Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain 90, 105 – 111. Takahashi, H., Shibata, M., Ohkubo, T., Saito, K., Inoki, R., 1987. Effect of neurotropin on hyperalgesia induced by prostaglandin E2, naloxone, melatonin and dark condition in mice. Japanese Journal of Pharmacology 43, 441 – 444. Ulugol, A., Aslantas, A., Karadag, H.C., Bulbul, E.D., Tuncer, A., Dokmeci, I., 2002. The effect of combined systemic administration of morphine and LNAME, a nitric oxide synthase inhibitor, on behavioral signs of neuropathic pain in rats. Neuroscience Research Communications 30, 143 – 153. Watson, C.P., 2000. The treatment of neuropathic pain: antidepressants and opioids. The Clinical Journal of Pain 16, S49 – S55. Woolf, C.J., Mannion, R.J., 1999. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959 – 1964. Yoon, Y.W., Sung, B., Chung, J.M., 1998. Nitric oxide mediates behavioral signs of neuropathic pain in an experimental rat model. NeuroReport 9, 367 – 372. Yu, C.X., Weng, S.M., Zhu, L.K., Peng, X.P., Chen, C.H., 1999. The analgesic effects of melatonin in rat and mice. Chinese Journal of Pain Medicine 5, 411 – 414. Yu, C.H., Zhu, C.B., Xu, S.F., Cao, X.D., Wu, G.C., 2000a. The analgesic effects of peripheral and central administration of melatonin in rats. European Journal of Pharmacology 403, 49 – 53. Yu, C.H., Zhu, C.B., Xu, S.F., Cao, X.D., Wu, G.C., 2000b. Selective MT2 melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neuroscience Letters 282, 161 – 164. Zimmermann, M., 1983. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16, 109 – 110.
Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the l-arginine–NO pathway and opioid system Ahmet Ulugol *, Dikmen Dokmeci, Gurkan Guray, Nese Sapolyo, Filiz Ozyigit, Melek Tamer Department of Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey Received 16 February 2005; accepted 21 July 2005
Abstract The present study was undertaken to determine the effects of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) melatonin on mechanical allodynia and thermal hyperalgesia in mice with partial tight ligation of the sciatic nerve, and how the nitric oxide (NO) precursor l-arginine and the opiate antagonist naloxone influence this effect. A plantar analgesic meter was used to assess thermal hyperalgesia, and nerve injury-induced mechanical hyperalgesia was assessed with von Frey filaments. 1 – 5 weeks following the surgery, marked mechanical allodynia and thermal hyperalgesia developed in neuropathic mice. Intracerebroventricular and intraperitoneal melatonin, with its higher doses, produced a blockade of thermal hyperalgesia, but not mechanical allodynia. Administration of both l-arginine and naloxone, at doses which produced no effect on their own, partially reversed antihyperalgesic effect of melatonin. These results suggest that although it has different effects on neuropathic pain-related behaviors, melatonin may have clinical utility in neuropathic pain therapy in the future. It is also concluded that l-arginine – NO pathway and opioidergic system are involved in the antihyperalgesic effect of melatonin in nerve-injured mice. D 2005 Elsevier Inc. All rights reserved. Keywords: Neuropathic pain; Allodynia; Hyperalgesia; Melatonin
Introduction Nerve injury that affects peripheral nerves leads to abnormal pain conditions referred to as neuropathic pain. Mechanical allodynia (nociceptive responses to normally innocuous stimuli) and thermal hyperalgesia (augmented pain intensity in response to normally painful stimuli) are two frequently seen clinical symptoms associated with neuropathic pain. Several animal models have recently been developed to investigate the mechanisms underlying this chronic pain state (Bennett and Xie, 1988; Kim and Chung, 1992; Seltzer et al., 1990). Most of these models have been developed in the rat; however, there is a need to adapt the rat models to the mouse to define the molecular basis and mechanisms of neuropathic pain. Partial tight ligation of the sciatic nerve in rats is a widely employed model, which produces spontaneous pain, allodynia and hyperalgesia, analogous to clinical conditions of neuropathic pain (Seltzer et al., * Corresponding author. Tel.: +90 532 4316449; fax: +90 284 2353925. E-mail address: [email protected] (A. Ulugol). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.07.002
1990; Seltzer, 1995); recently the same model has also been applied in mice (Malmberg and Basbaum, 1998). Neuropathic pain is generally accepted to be particularly insensitive to drug treatment, including the potent analgesics, opioids (Benedetti et al., 1998; MacFarlane et al., 1997; Watson, 2000). Tricyclic antidepressants and gabapentin are often prescribed, with variable responses and effectiveness (MacFarlane et al., 1997). Although considerable efforts have been spent on the discovery of novel analgesics for the treatment of chronic pain syndromes, there is not much improvement observed, and there seems to be an urgent need for effective drugs in these cases. Melatonin (N-acetyl-5-methoxytryptamine) is known as a neurohormone that is synthesized and secreted mainly by the pineal gland from the amino acid precursor l-tryptophan. Although the physiological significance of melatonin is not yet fully understood, the involvement in circadian rhythms is the best described function of the hormone (Pacchierotti et al., 2001). Melatonin has also been shown to be involved in some psychopharmacological effects including the sedative/hypnotic,
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anticonvulsant and anti-anxiety effects (Geoffriau et al., 1998; Golombek et al., 1996; Sugden, 1983). N-methyl-d-aspartate (NMDA) receptors and the l-arginine –NO pathway, opioidergic and GABAergic systems have been shown to play a role in these behavioral effects of melatonin (Golombek et al., 1991, 1996; Mantovani et al., 2003). Moreover, a number of reports indicate that the hormone exerts a potent and long-lasting antinociceptive effect (Golombek et al., 1991; Lakin et al., 1981; Sugden, 1983; Yu et al., 1999, 2000b). However, no report so far has addressed the modulation of neuropathic pain behaviors, such as allodynia and hyperalgesia, by melatonin. Therefore, the aim of this study was, firstly, to determine whether melatonin affects mechanical allodynia and thermal hyperalgesia in sciatic nerve-ligated neuropathic mice and, secondly, to analyze to what extent the activity of melatonin can be inhibited by the NO precursor l-arginine and the opiate antagonist naloxone.
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min before starting the experiments. To minimize the differences in technique, the same person performed each operation. Assessment of mechanical allodynia Mechanical allodynia thresholds were assessed, as described previously (Hao et al., 2000; Gustafsson et al., 2003). Briefly, eight von Frey filaments, with approximately equal logarithmic incremental bending forces, were chosen (von Frey numbers: 2.44, 2.83, 3.22, 3.61, 4.08, 4.31, 4.56, 4.93; equivalent to 0.04, 0.07, 0.16, 0.4, 1, 2, 4, 8 g, respectively). Each hair was pressed perpendicularly against the paw until slight buckling was observed. The area tested was the middle area between the footpads of the plantar surface of the hindpaw. Testing was initiated with the 0.04 g hair and kept on in an ascending order of force. The withdrawal threshold was defined as the force at which the mouse withdrew the paw from at least three of the five consecutive applications.
Materials and methods Assessment of thermal hyperalgesia This study was conducted according to the guidelines of the Ethical Committee of the International Association for the Study of Pain (Zimmermann, 1983), and had been approved by the ‘‘Animal Care Ethics Committee’’ of our faculty. Animals Male bulb-c albino mice (Center of the Laboratory Animals, Eczacibasi-Turkey), weighing 20 –25 g at time of operation, were used for the experiments. The mice were housed ten in a cage in a quiet room and had free access to standard laboratory food and tap water. The ambient temperature was kept at 22 T 1 -C, since lowering ambient temperature has been shown to augment abnormalities in pain-related behaviors of neuropathic pain (Sato et al., 2000). Surgery Under ketamine/xylazine anesthesia (100 mg/kg/10 mg/kg, i.p.), a partial nerve ligation of the sciatic nerve was made by tightly tying 1/3 to 1/2 of the dorsal portion of the sciatic nerve, using a similar procedure to that described for rats by Seltzer et al. (1990) and for mice by Malmberg and Basbaum (1998). In shamoperated mice the nerve was exposed, but not ligated. After confirming a complete hemostasis, the muscle and the skin was sutured and the mice were returned to their cages after full recovery from anesthesia. Mice with this nerve injury have been shown to develop mechanical and thermal allodynia and hyperalgesia and are used as a model for neuropathic pain (Bortalanza et al., 2002; Malmberg and Basbaum, 1998; Shields et al., 2003). Behavioral testing The mice were placed under a glass cover on a metal mesh floor for assessments of tactile allodynia and in a plexiglass box of a Plantar test apparatus for assessments of mechanical hyperalgesia, and adapted to testing environment for at least 15
Thermal nociceptive threshold to radiant heat was quantified using the method of Hargreaves et al. (1988). Briefly, mice were placed in a plexiglass box on top of the temperature maintained (30 T 0.1 -C) glass surface of the stimulator (Maycom, Turkey). A beam of radiant heat was applied through the glass to the plantar surface of the hind paw. The paw withdrawal latency, defined as the time from onset of the radiant heat to the withdrawal of the paw, was detected with a photocell and a timer. The radiant heat source was adjusted to result in pre-injection latencies of 12– 13 s. A maximal cut-off of 20 s was used to prevent tissue damage. Experimental design Tests took place 2 – 3 weeks after tight ligation of the sciatic nerve. Mechanical allodynia and thermal hyperalgesia thresholds were assessed immediately before, and at 0.5, 1, and 2 h after drug injections. After testing different doses of intraperitoneal (30, 60, 120 mg/kg, i.p.) and intracerebroventricular (0.001, 0.01, 0.1 nmol, i.c.v.) melatonin, concomitant administrations of l-arginine (200 mg/kg, i.p.; 80 Ag, i.c.v.) and naloxone (1 mg/kg, i.p.; 10 Ag, i.c.v.) with the effective doses of melatonin (120 mg/kg, i.p.; 0.1 nmol, i.c.v.) was investigated. The effectiveness of l-arginine and naloxone on mechanical allodynia and thermal hyperalgesia, when administered alone, were also evaluated. Drugs Melatonin and l-arginine were obtained from Sigma Chemical Co., while naloxone was purchased from Research Biochemicals Inc. All chemicals were dissolved in isotonic NaCl, and i.p. administrations were made in a volume of 0.1 ml/100 g body weight. For i.c.v. administration, the drugs were injected in the necessary dosage, in a volume of 5 Al/mouse using a Hamilton’s microlitre syringe following the method of
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Fig. 1. Changes in withdrawal latency to thermal stimulation (A) and in withdrawal threshold to mechanical stimulation with von Frey hairs (B) in sciatic nerveligated and sham-operated mice. Withdrawal thresholds and latencies were assessed before (Pre) and 1 – 5 weeks after the operation. (*P < 0.05, compared to corresponding values in the control group; ANOVA followed by Newman – Keuls test).
Haley and McCormick (1957). The reliability of the method was confirmed by pilot studies using injection of India ink and macroscopically observing its diffusion into various parts of the brain after sectioning. The site of injection was 1.5 mm from either side of the midline on a line drawn through the anterior base of the ears. After grasping the head of the mouse firmly, the needle of the 10 Al Hamilton syringe was inserted perpendicularly 3 mm through the skull into the brain. Then, the solution was injected slowly, in 20 s, into the right lateral ventricle. For either i.p. or i.c.v. administrations, the equivalent volume of vehicle was administered to the control groups. Statistical analysis Data were analyzed by analysis of variance (ANOVA) followed by Newman – Keuls test. Values of P < 0.05 were considered to be significant. All data are expressed as mean T SEM. Results Effects of tight ligation of the sciatic nerve As described previously (Bortalanza et al., 2002; Malmberg and Basbaum, 1998; Shields et al., 2003), mice subjected to tight
ligation of the sciatic nerve developed pain-related behavior, marked as mechanical allodynia and thermal hyperalgesia. Withdrawal threshold (assessing mechanical allodynia) and withdrawal latencies (assessing thermal hyperalgesia) during the 5-week period after the surgery are shown in Fig. 1A,B. Prior to operation, mice rarely responded to thinner von Frey hairs and were slower when withdrawing their hind paws from the radiant heat beam; paw withdrawal threshold for mechanical allodynia and withdrawal latency for thermal hyperalgesia being 1.7 T 0.1 and 13.1 T1.2, respectively (Fig. 1A,B). One to five weeks after nerve injury, significant reduction both in paw withdrawal thresholds to von Frey filaments and in withdrawal latencies to radiant heat were observed (Fig. 1A,B). Effects of i.p. and i.c.v. melatonin on mechanical allodynia and thermal hyperalgesia With its highest doses, both i.p. (120 mg/kg) and i.c.v. (0.1 nmol) administrations of melatonin reduced paw withdrawal latencies in response to radiant heat stimulation of the injured hindpaw, compared to corresponding values in the control group ( p < 0.05, Fig. 2A,B). No significant drug effect was observed 2 h post drug administrations (Fig. 2A,B). In the case of mechanical allodynia, neither i.p. nor i.c.v. melatonin had any effect on the withdrawal thresholds to von Frey hairs,
Fig. 2. Effects of i.c.v. (A) i.p. (B) injections of vehicle (n = 6) and three doses of melatonin (0.001 – 0.1 nmol, i.c.v; 30 – 120 mg/kg, i.p.; n = 6 for each dose) on thermal hyperalgesia. Preoperative (Pre) values were determined before the operation. Withdrawal latencies were also assessed before (0) and 0.5, 1, and 2 h after drug administrations. (*P < 0.05, compared to corresponding values in the control group; ANOVA followed by Newman – Keuls test).
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Fig. 3. Antihyperalgesic effect of i.c.v. (A) and i.p. (B) melatonin (Mel, 0.1 nmol, i.c.v.; 120 mg/kg, i.p.), and prevention of this effect by l-arginine (l-arg, 80 Ag, i.c.v.; 200 mg/kg, i.p.) and naloxone (Nal, 10 Ag, i.c.v.; 1 mg/kg, i.p.). Withdrawal latencies were assessed 0.5, 1, and 2 h after drug administrations. n = 6 – 7 per group. (*P < 0.05, compared to corresponding values in the control group; +P < 0.05, compared to corresponding values in the combination group; ANOVA followed by Newman – Keuls test).
compared to the respective pre-injection baseline value. No signs of side effects such as sedation or motor impairment were noted following either the surgery or the melatonin administrations at any dose. Effects of l -arginine and naloxone on melatonin administration Concomitant administrations of both l-arginine (200 mg/kg, i.p.; 80 Ag, i.c.v.) and naloxone (1 mg/kg, i.p.; 10 Ag, i.c.v.), at doses which produced no effect on their own when administered either i.p. or i.c.v., reduced the effect of melatonin (120 mg/kg, i.p.; 0.1 nmol, i.c.v.) on thermal hyperalgesia (Fig. 3A,B). Their influence on the effect of melatonin on mechanical allodynia is not determined, since melatonin did not affect this neuropathic pain behavior. Discussion Neuropathic pain is very difficult to manage clinically. Tricyclic antidepressants and anticonvulsant drugs are often prescribed, but both are associated with significant use-limiting adverse effects (MacFarlane et al., 1997; Watson, 2000; Woolf and Mannion, 1999). The potent analgesics, opioids, on the other hand, are effective only in some conditions of neuropathic pain, such as postherpetic neuralgia and diabetic neuropathy. Most of the other chronic pain conditions are still considered to be relatively insensitive to opioid treatment (Benedetti et al., 1998; MacFarlane et al., 1997; Watson, 2000), suggesting the need for new effective drugs in neuropathic states. In addition to new effective drugs, new mouse models will also be necessary both to perform genetic studies readily and to explore the molecular basis and mechanisms of neuropathic pain. Mice used in our study exerted significant mechanical allodynia and thermal hyperalgesia after the surgery. Although Shields et al. (2003) did not observe thermal hyperalgesia after similar operation; our results are consistent with those of Malmberg and Basbaum (1998). There are few reports indicating hyperalgesic or no effect of melatonin on analgesia (Psarakis et al., 1988; Takahashi et al.,
1987), and attenuation of morphine analgesia by melatonin (Datta et al., 1982). Conversely, accumulating evidence indicates that melatonin has a potent and long-lasting antinociceptive activity (Golombek et al., 1991, 1996; Lakin et al., 1981; Sugden, 1983; Yu et al., 1999, 2000b). Apart from its known efficacy on acute pain states, the effects of melatonin on behavioral signs of neuropathic pain, such as allodynia and hyperalgesia, have not been studied. Sugden has reported that melatonin had very low acute toxicity when administered to mice and rats by various routes (1983). Taken together, melatonin seems to be a promising drug for the treatment of neuropathic pain. Our findings support this suggestion, since we also did not observe any signs of side effects such as sedation or motor impairment at any dose of melatonin, and showed for the first time the effectiveness of melatonin in a chronic pain condition. Several effects of melatonin, including analgesia, are known to be time-dependent. Although melatonin has been shown to exhibit maximal analgesic effects at the light– dark transitional period (Golombek et al., 1991, 1996), there are reports indicating that it is also efficacious at the mid-light period, but with its pharmacological doses (Golombek et al., 1991; Lakin et al., 1981; Sugden, 1983). Melatonin augmentation of morphine induced analgesia in the daytime has also been reported (Kavaliers et al., 1983). These reports are in line with our findings, since we observed the anti-hyperalgesic effect of melatonin during the mid-light period, only with its higher doses tested. Despite intensive investigation, the precise effects of larginine –NO – cGMP pathway on acute and chronic pain states remain unclear. There are observations indicating that larginine –NO – cGMP pathway exerts a hyperalgesic action; however, it is generally believed that it has an antinociceptive effect (Meller et al., 1992; Moore et al., 1991). It has also been shown that NO mediates behavioral signs of neuropathic pain (Yoon et al., 1998), and that NG-nitro-l-arginine-methyl ester (L-NAME), a NO synthase inhibitor, inhibited mechanical and cold allodynia in neuropathic rats (Ulugol et al., 2002). Moreover, morphine has been shown to induce antinociception by the activation of the l-arginine – NO – cGMP pathway
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(Granados-Soto et al., 1997). Recently, it has been indicated that melatonin exerts an antidepressant-like effect in the mouse tail suspension test, which seems to be mediated through an interaction with NMDA receptors and l-arginine –NO pathway (Mantovani et al., 2003). Taken together, although it is generally assumed that melatonin exerts responses through activation of melatonin receptors (Yu et al., 2000b); one might expect l-arginine –NO – cGMP pathway to play a role in melatonin analgesia. Opioidergic and GABAergic systems have also been shown to play a role in the behavioral effects of melatonin (Golombek et al., 1991, 1996; Mantovani et al., 2003). Opioid or central-type benzodiazepine antagonism has been shown to inhibit melatonin analgesia, and GABAergic system has been shown to play a role in the inhibitory (sedation, hypnotic activity, antinociceptive, anticonvulsive, anti-anxiety effects) effects of melatonin (Golombek et al., 1991, 1996). It has also been suggested that melatonin promotes the release of h-endorphin in the brain, which may be one of the mechanisms of action of melatonin to induce analgesia (Yu et al., 2000a). Similar to these results, we observed that concomitant administrations of both l-arginine and naloxone reduce the effect of melatonin on thermal hyperalgesia, indicating the role of l-arginine – NO pathway and opioidergic system in the anti-hyperalgesic effect of melatonin. Mechanical allodynia and thermal hyperalgesia, two principal manifestations of neuropathic pain, are suggested to be mediated through separate mechanisms and neuronal pathways; the exact mechanisms underlying these behavioral signs of neuropathic pain remain poorly understood and the drugs may affect these manifestations conversely. Morphine, for example, has been shown to block small (C and Ay) but not large diameter (Ah) fibre evoked responses into the dorsal horn (Dickenson and Sullivan, 1986; Le Bars et al., 1979). Tactile allodynia has been suggested to be mediated through large diameter, Ah-afferent fibers, whereas thermal hyperalgesia is likely to be mediated through small diameter, unmyelinated high threshold C-fibers (Ossipov et al., 1999; Shir and Seltzer, 1998). Accordingly, thermal hyperalgesia has been shown to be more sensitive to morphine administration than dynamic allodynia, and the failure of morphine to block dynamic allodynia suggests that it is mediated by Ah-fibers (Field et al., 1999; Sun et al., 2001). Taken together, mechanical allodynia seems to be much more difficult to manage; our findings are also in line with this suggestion, since melatonin exerted antihyperalgesic, but not antiallodynic effect. Conclusion As a result, our findings show that both i.c.v. and i.p. melatonin, with its higher doses, block thermal hyperalgesia, but not mechanical allodynia in neuropathic mice, and may be useful for the clinical management of chronic painful situations. Melatonin effect on thermal hyperalgesia is mediated, at least partially, by l-arginine – NO pathway and opioidergic system.
Acknowledgement The authors wish to thank Eczacibasi-Turkey for the mice. References Benedetti, F., Vighetti, S., Amanzio, M., Casadio, C., Oliaro, A., Bergamasco, B., Maggi, G., 1998. Dose – response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 74, 205 – 211. Bennett, G.J., Xie, Y.K., 1988. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87 – 107. Bortalanza, L., Ferreira, J., Hess, S.C., Monache, F.D., Yunes, R.A., Calixto, J.B., 2002. Anti-allodynic action of the tormentic acid, a triterpene isolated from plant, against neuropathic and inflammatory persistent pain in mice. European Journal of Pharmacology 453, 203 – 208. Datta, P.C., Sandman, C.A., Hoehler, F.K., 1982. Attenuation of morphine analgesia by (-MSH, MIF-I, melatonin and naloxone in the rat. Peptides 3, 433 – 437. Dickenson, A.H., Sullivan, A.F., 1986. Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurons in the rat dorsal horn. Pain 24, 211 – 222. Field, M.J., Bramwell, S., Hughes, J., Singh, L., 1999. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signaled by distinct primary sensory neurons? Pain 83, 303 – 311. Geoffriau, M., Brun, J., Chazot, G., Claustrat, B., 1998. The physiology and pharmacology of melatonin in humans. Hormone Research 49, 136 – 141. Golombek, D.A., Escolar, E., Burin, L.J., De-Brito-Sanchez, M.G., Cardinali, D.P., 1991. Time-dependent melatonin analgesia in mice: inhibition by opiate or benzodiazepine antagonism. European Journal of Pharmacology 194, 25 – 30. Golombek, D.A., Pevet, P., Cardinali, D.P., 1996. Melatonin effects on behavior: possible mediation by the central GABAergic system. Neuroscience and Biobehavioral Reviews 20, 403 – 412. Granados-Soto, V., Rufino, M.O., Lopes, L.D.G., Ferreira, S.H., 1997. Evidence for the involvement of the nitric oxide – cGMP pathway in the antinociception of morphine in the formalin test. European Journal of Pharmacology 340, 177 – 180. Gustafsson, H., Flood, K., Berge, O.G., Brodin, E., Olgart, L., Stiller, C.O., 2003. Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Experimental Neurology 182, 427 – 434. Haley, T.J., McCormick, W.G., 1957. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. British Journal of Pharmacology 12, 12 – 15. Hao, J.X., Blakeman, K.H., Yu, W., Hultenby, K., Xu, X.J., Wiesenfeld-Hallin, Z., 2000. Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve. Experimental Neurology 163, 231 – 238. Hargreaves, K., Dubner, R., Brown, F., Flores, C., Joris, J., 1988. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77 – 88. Kavaliers, M., Hirst, M., Teskey, G.C., 1983. Ageing, opioid analgesia and the pineal gland. Life Sciences 32, 2279 – 2287. Kim, S.H., Chung, J.M., 1992. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355 – 363. Lakin, M.L., Miller, C.H., Stott, M.L., Winters, W.D., 1981. Involvement of the pineal gland and melatonin in murine analgesia. Life Sciences 29, 2543 – 2551. Le Bars, D., Rivot, J.P., Guilbaud, G., Menetrey, D., Besson, J.M., 1979. The depressive effect of morphine on the C-fibre response of dorsal horn neurons in the spinal rat pretreated or not by pCPA. Brain Research 176, 337 – 353. MacFarlane, B.V., Wright, A., O’Callaghan, J., Benson, H.A.E., 1997. Chronic neuropathic pain and its control by drugs. Pharmacology & Therapeutics 75, 1 – 19.
A. Ulugol et al. / Life Sciences 78 (2006) 1592 – 1597 Malmberg, A.B., Basbaum, A.I., 1998. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76, 215 – 222. Mantovani, M., Pertile, R., Calixto, J.B., Santos, A.R.S., Rodrigues, A.L.S., 2003. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-Daspartate receptors and the L-arginine-nitric oxide pathway. Neuroscience Letters 343, 1 – 4. Meller, S.T., Pechman, P.S., Gebhart, G.F., Maves, T.J., 1992. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 50, 7 – 10. Moore, P.K., Oluyomi, A.O., Babbedge, R.C., Wallace, P., Hart, S.L., 1991. LNG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. British Journal of Pharmacology 102, 198 – 202. Ossipov, M.H., Bian, D., Malan Jr., T.P., Lai, J., Porreca, F., 1999. Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats. Pain 79, 127 – 133. Pacchierotti, C., Lapichino, S., Bossini, L., Pieraccini, F., Castrogiovanni, P., 2001. Melatonin in psychiatry disorders: a review on the melatonin involvement in psychiatry. Frontiers in Neuroendocrinology 22, 18 – 32. Psarakis, S., Brown, G.M., Grota, L.J., 1988. Analgesia induced by N-acetylserotonin in the central nervous system. Life Sciences 42, 1109 – 1116. Sato, J., Morimae, H., Takanari, K., Seino, Y., Okada, T., Suzuki, M., Mizumura, K., 2000. Effects of lowering ambient temperature on painrelated behaviors in a rat model of neuropathic pain. Experimental Brain Research 133, 442 – 449. Seltzer, Z., 1995. The relevance of animal neuropathy models for chronic pain in humans. Neurosciences 7, 211 – 219. Seltzer, Z., Dubner, R., Shir, Y., 1990. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205 – 218. Shields, S., Eckert, W.A., Basbaum, A.I., 2003. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. The Journal of Pain 4, 465 – 470.
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Shir, Y., Seltzer, Z., 1998. A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neuroscience Letters 115, 62 – 67. Sugden, D., 1983. Psychopharmacological effects of melatonin in mouse and rat. The Journal of Pharmacology and Experimental Therapeutics 227, 587 – 591. Sun, H., Ren, K., Zhong, C.M., Ossipov, M.H., Malan Jr., T.P., Lai, J., Porreca, F., 2001. Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain 90, 105 – 111. Takahashi, H., Shibata, M., Ohkubo, T., Saito, K., Inoki, R., 1987. Effect of neurotropin on hyperalgesia induced by prostaglandin E2, naloxone, melatonin and dark condition in mice. Japanese Journal of Pharmacology 43, 441 – 444. Ulugol, A., Aslantas, A., Karadag, H.C., Bulbul, E.D., Tuncer, A., Dokmeci, I., 2002. The effect of combined systemic administration of morphine and LNAME, a nitric oxide synthase inhibitor, on behavioral signs of neuropathic pain in rats. Neuroscience Research Communications 30, 143 – 153. Watson, C.P., 2000. The treatment of neuropathic pain: antidepressants and opioids. The Clinical Journal of Pain 16, S49 – S55. Woolf, C.J., Mannion, R.J., 1999. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959 – 1964. Yoon, Y.W., Sung, B., Chung, J.M., 1998. Nitric oxide mediates behavioral signs of neuropathic pain in an experimental rat model. NeuroReport 9, 367 – 372. Yu, C.X., Weng, S.M., Zhu, L.K., Peng, X.P., Chen, C.H., 1999. The analgesic effects of melatonin in rat and mice. Chinese Journal of Pain Medicine 5, 411 – 414. Yu, C.H., Zhu, C.B., Xu, S.F., Cao, X.D., Wu, G.C., 2000a. The analgesic effects of peripheral and central administration of melatonin in rats. European Journal of Pharmacology 403, 49 – 53. Yu, C.H., Zhu, C.B., Xu, S.F., Cao, X.D., Wu, G.C., 2000b. Selective MT2 melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neuroscience Letters 282, 161 – 164. Zimmermann, M., 1983. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16, 109 – 110.