Oral and spinal melatonin reduces tactile allodynia in... : PAIN (original) (raw)
1. Introduction
Melatonin (_N_-acetyl-5-methoxytryptamine) is a hormone synthesized primarily in the mammalian pineal gland and secreted into the bloodstream (Vanecek, 1998). This hormone is involved in several biological functions, including circadian rhythms, sleep and analgesia (Morgan et al., 1994; Vanecek, 1998; von Gall et al., 2002; Simonneaux and Ribelayga, 2003; Zahn et al., 2003). There is evidence that systemic (Golombek et al., 1991; Raghavendra et al., 2000; Yu et al., 2000a; Ulugol et al., 2006) or central (Yu et al., 2000a; Noseda et al., 2004; Onal et al., 2004; Tu et al., 2004; Ulugol et al., 2006; Wang et al., 2006) administration of melatonin produces a dose-dependent antinociception in models of acute (Lakin et al., 1981; Golombek et al., 1991; Yu et al., 2000a; El-Shenawy et al., 2002; Naguib et al., 2003; Dhanaraj et al., 2004) and inflammatory (Cuzzocrea et al., 1997; Raghavendra et al., 2000; Pang et al., 2001; Bilici et al., 2002; El-Shenawy et al., 2002; Ray et al., 2004; Padhy and Kumar, 2005; Wang et al., 2006) pain in animals.
Melatonin significantly depresses nociceptive discharges of spinal dorsal horn neurons that follow stimulation of C fibers (Laurido et al., 2002). Moreover, melatonin inhibits synaptic potentiation (wind-up) in the spinal cord (Noseda et al., 2004) and it inhibits voltage-activated calcium currents in dorsal root ganglion neurons (Ayar et al., 2001). Several autoradiographic studies have shown that melatonin receptors are present in lamina I–V and lamina X of the spinal cord (Wan and Pang, 1993, 1994; Pang et al., 1997). In addition, reverse-transcriptase polymerase chain reaction studies have demonstrated the presence of transcripts for MT1 and MT2 melatonin receptors in the dorsal horn of the spinal cord (Zahn et al., 2003). Based on this evidence, we have hypothesized that the spinal or supraspinal melatonin system might be involved in the modulation of neuropathic pain. Therefore, the purpose of the present work was to assess the possible antiallodynic effect of melatonin after intrathecal and oral administration in rats submitted to the ligation of the L5/L6 spinal nerves. In addition, using available pharmacological tools, the possible participation of MT2 and opioid receptors in melatonin-induced antiallodynic activity was also assessed.
Part of this work has previously been published in the abstract form (Ambriz-Tututi and Granados-Soto, 2006).
2. Materials and methods
2.1. Animals
Female Wistar rats aged 6–7 weeks (weight range, 140–160g) from our own breeding facilities were used in this study. Animals had free access to food and drinking water before experiments. Efforts were made to minimize animal suffering and to reduce the number of animals used. Rats were used once only. Experiments were carried out at the same hours of the day (11:00–16:00h). All experiments followed the Guidelines on Ethical Standards for Investigation of Experimental Pain in Animals (Zimmermann, 1983). Additionally, the Institutional Animal Care and Use Committee approved the study (Centro de Investigación y de Estudios Avanzados, México, D.F., Mexico).
2.2. Measurement of antiallodynic activity
Rats were prepared according to the method of Kim and Chung (1992). Animals were anesthetized with a mixture of ketamine/xylazine (45/12mg/kgi.p.). After surgical preparation and exposure of the dorsal vertebral column, the left L5 and L6 spinal nerves were exposed and tightly ligated with 6–0 silk suture distal to the dorsal root ganglion. For sham operated rats, the nerves were exposed but not ligated. The incisions were closed, and the animals were allowed to recover for 10 days. Rats exhibiting motor deficiency (such as paw-dragging) were discarded from testing (less than 5%).
Tactile allodynia was determined by measuring paw withdrawal threshold in response to probing with a series of calibrated fine filaments (von Frey filaments). The strength of the von Frey stimuli ranged from 0.4 to 15g. Withdrawal threshold was determined by increasing and decreasing stimulus strength eliciting paw withdrawal (Chaplan et al., 1994). The stimulus intensity required to produce a response in 50% of the applications for each animal was defined as “50% withdrawal threshold”. All nerve-ligated rats were verified to be allodynic (responding to a stimulus of less than 4g). Rats not demonstrating allodynia were not further studied (less than 5%).
2.3. Spinal surgery
Ten days after surgery rats were submitted to a second surgery for insertion of a spinal catheter. Rats were anesthetized with a ketamine/xylazine mixture (45/12mg/kgi.p.), placed in a stereotaxic head holder, and the atlantooccipital membrane exposed (Yaksh and Rudy, 1976). The membrane was pierced, and a PE-10 catheter (7.5cm) was passed intrathecally to the level of the thoracolumbar junction and the wound was sutured. Rats were allowed to recover from surgery for at least 5 days in individualized cages before use. Animals showing any signs of motor impairment were euthanized in a CO2 chamber.
2.4. Drugs
Melatonin (_N_-acetyl-5-methoxytryptamine) was obtained from Research Biochemical International (Natick, MA, USA). 4P-PDOT (4-phenyl-2-propionamidotetralin) was purchased from Tocris Bioscience. Luzindole (_N_-[2-[2-(phenylmethyl)-1_H_-indol-3-yl]ethyl]acetamide _N_-acetyl-2-benzyltryptamine) and naltrexone were obtained from Sigma (St. Louis, MO, USA). For oral administration, melatonin and 4P-PDOT were dissolved in 10% alcohol. For intrathecal administration, melatonin, 4P-PDOT and luzindole were dissolved in 20% dimethylsulfoxide (DMSO). Naltrexone was dissolved in saline. Ethanol 10% was used as vehicle for oral administration, whereas 20% DMSO was used as vehicle for intrathecal administration.
2.5. Experimental protocols
For the systemic study, animals received oral administration of vehicle or increasing doses of melatonin (37.5–300mg/kg) 30min before assessment of withdrawal threshold in neuropathic rats. For the spinal study, rats received a spinal injection of vehicle or increasing doses of melatonin (3–100μg) 30min before evaluation of withdrawal threshold in spinal nerve injured rats. To determine whether the melatonin-induced antiallodynic effect was mediated by the activation of the MT2 receptor using both routes of administration, the effect of pretreatment (−40min) with the appropriate vehicle (see above), luzindole (intrathecal: 1–100μg) or 4P-PDOT (oral: 0.01–1mg/kg; intrathecal: 0.1–10μg) on the antiallodynic effect induced by melatonin (−30min, oral: 150mg/kg; intrathecal: 100μg) was assessed. To determine whether melatonin-induced antiallodynia was mediated by opioid receptor activation in both routes of administration, the effect of treatment (−40min) with saline or naltrexone (subcutaneous: 1mg/kg; intrathecal: 50μg) on the antiallodynic effect induced by melatonin (−30min, oral: 150mg/kg; intrathecal: 100μg) was assessed. In addition, to determine whether melatonin-induced antiallodynia after oral administration was mediated by spinal MT2 receptor activation, the effect of intrathecal pretreatment (−40min) with 4P-PDOT (10μg) on the antiallodynic effect induced by oral melatonin (−30min, 150mg/kg) was assessed. Moreover, the effect of intrathecal melatonin (100μg) after pretreatment with the combination of small doses of 4P-PDOT (0.1μg) and naltrexone (0.5μg) was assessed in order to determine the possible additive effect of both antagonists.
Systemic drugs were given by oral administration (2ml/kg). Each rat received two oral administrations. Contrariwise, intrathecal drugs were injected in a volume of 10μl. Each rat received two spinal injections and appropriate controls for the injections and vehicles were performed before starting the formal study. For all routes of administration, doses were selected based on previous reports (Yu et al., 2000a,b; Noseda et al., 2004; Tu et al., 2004) and on pilot experiments in our laboratory. The observer was unaware of the treatment in each animal.
2.6. Motor co-ordination test
Since melatonin receptors are present in the ventral as well as in the dorsal horn of the spinal cord (Zahn et al., 2003), the effect of the greatest tested doses of melatonin on motor function was assessed. Four independent groups of rats (_n_=6, each) were examined for motor co-ordination in a treadmill apparatus (rotarod test) before and after receiving melatonin 300mg/kg (po), 100μg (it) or vehicle for oral and intrathecal administration. Animals were placed upon a cylinder (7cm diameter) rotating at a speed of 10rpm. Rats were trained to walk on the cylinder for three consecutive sessions and on the fourth, they received the drug or vehicle treatment (time 0) and the number of falls during a 5min period was counted after 45min.
2.7. Data analysis and statistics
All experimental results are given as means±SEM for six animals per group. Curves were constructed plotting the threshold for paw withdrawal as a function of time. An increase of 50% withdrawal threshold was considered as an antiallodynic effect. Area under the 50% withdrawal threshold against time curve (AUC) for a period of 240min was calculated by the trapezoidal method. One- or two-way analysis of variance (ANOVA), followed by Tukey’s test, was used to compare differences between treatments. The Kruskal–Wallis analysis of variance was used to test differences in rats submitted to the rotarod test. Differences were considered to reach statistical significance when P<0.05.
3. Results
3.1. Oral and intrathecal antiallodynic effect of melatonin
Ligation of L5/L6 spinal nerves produced a clear-cut tactile allodynia in rats submitted to the surgery compared to the sham operated rats (Fig. 1a). Oral (300mg/kg) or intrathecal (100μg) administration of melatonin, but not vehicle, significantly (P<0.05) reversed tactile allodynia induced by ligation of L5/L6 spinal nerves (Fig. 1b). In addition, systemic (ED50 143.2±8.4mg/kg; Fig. 2a) or intrathecal (ED50 17.8±0.9μg; Fig. 2b) administration of melatonin produced a dose-dependent antiallodynic effect (P< 0.05), although the spinal antiallodynic effect was greater than that observed after oral administration (Figs. 1b and 2).
(a) Time course of paw withdrawal threshold in rats submitted to the ligation of L5/L6 spinal nerves compared to sham-operated rats. Withdrawal threshold was assessed at day 1, 3, 5, 7, 9 and 12 after surgery. (b) Time course of the antiallodynic effect observed after bolus administration of melatonin in rats previously submitted to spinal nerve ligation. The sham group (black triangles) is placed as a reference for the maximum possible effect. In all cases data are presented as means ± SEM for six animals. A significant difference (P < 0.05, by two-way ANOVA followed by the Tukey’s test) was observed between vehicle and either oral or intrathecal melatonin groups 30 min after starting threshold evaluations and up to 240 min. ∗ Indicating significant differences were omitted for the sake of clarity.
Dose–response curves for the antiallodynic effect of oral (a) and intrathecal (b) administration of melatonin in rats submitted to ligation of L5/L6 spinal nerves. Rats were treated with vehicle or increasing doses of melatonin 30 min before starting threshold evaluations. Data are expressed as the area under the 50% withdrawal threshold against time curve (AUC). Bars are the mean ± SEM for six to seven animals. ∗ Significantly different from the vehicle group, as determined by one-way ANOVA followed by the Tukey’s test.
3.2. Effect of luzindole on melatonin-induced spinal antiallodynic activity
Intrathecal administration of the preferential MT2 receptor antagonist luzindole (Dubocovich et al., 1997; Browning et al., 2000) did not modify tactile allodynia in neuropathic rats. However, the intrathecal treatment with luzindole (1–100μg), but not vehicle, significantly (P<0.05) diminished in a dose-dependent manner the antiallodynic effect induced by the spinal administration of melatonin (100μg, Fig. 3).
Effect of luzindole on melatonin-induced spinal antiallodynic activity in rats submitted to ligation of L5/L6 spinal nerves. Rats were treated with intrathecal vehicle or increasing doses of luzindole (−40 min) and melatonin (−30 min) before starting threshold evaluations. Data are expressed as the area under the 50% withdrawal threshold against time curve (AUC). Bars are the mean ± SEM for six to seven animals. ∗ Significantly different from the melatonin group, as determined by one-way ANOVA followed by the Tukey’s test.
3.3. Effect of 4P-PDOT on melatonin-induced antiallodynic activity
Oral administration of the highly selective MT2 receptor antagonist (Dubocovich et al., 1997; Browning et al., 2000) 4P-PDOT (0.01–1mg/kg) did not modify tactile allodynia in neuropathic rats by itself, but dose-dependently (P<0.05) diminished the antiallodynic activity induced by oral administration of melatonin (150mg/kg, Fig. 4a). Moreover, intrathecal treatment with 4P-PDOT (0.1–10μg), but not vehicle, significantly (P<0.05) diminished the antiallodynic effect induced by the spinal administration of melatonin (100μg, Fig. 4b). At the greatest tested dose, 4P-PDOT (1mg/kg, po or 10μg, it) did not modify tactile allodynia in neuropathic rats (Fig. 4a and b).
Effect of 4P-PDOT on melatonin-induced antiallodynic activity in rats submitted to ligation of L5/L6 spinal nerves after oral (a) and intrathecal (b) administration. Rats were treated with vehicle or increasing doses of 4P-PDOT (−40 min) and melatonin (−30 min) before starting threshold evaluations. Data are expressed as the area under the 50% withdrawal threshold against time curve (AUC). Bars are the mean ± SEM for six to seven animals. ∗ Significantly different from the melatonin group, as determined by one-way ANOVA followed by the Tukey’s test.
3.4. Effect of naltrexone on melatonin-induced antiallodynic activity
Subcutaneous (1mg/kg) or intrathecal (0.5–50μg) administration of the non-selective opioid receptor antagonist naltrexone significantly (P<0.05) diminished the antiallodynic activity induced by either oral (150mg/kg) or intrathecal (100μg) administration of melatonin (Fig. 5). In contrast, naltrexone, at the greatest tested doses (1mg/kg or 50μg), did not modify tactile allodynia in the rats (Fig. 5).
Effect of subcutaneous (a) or intrathecal (b) naltrexone on either oral or intrathecal melatonin-induced antiallodynic activity in rats submitted to ligation of L5/L6 spinal nerves. Rats were treated with vehicle or naltrexone (−40 min) and melatonin (−30 min) before starting threshold evaluations. Data are expressed as the area under the 50% withdrawal threshold against time curve (AUC). Bars are the mean ± SEM for six to seven animals. ∗ Significantly different from the melatonin group, as determined by one-way ANOVA followed by the Tukey’s test.
3.5. Effect of the intrathecal administration of 4P-PDOT and 4P-PDOT plus naltrexone on oral and intrathecal melatonin-induced antiallodynic activity, respectively
Intrathecal treatment with 4P-PDOT (10μg) significantly (P<0.05) diminished the antiallodynic effect induced by the oral administration of melatonin (150mg/kg, Fig. 6a). In addition, the mixture of small doses of 4P-PDOT (0.1μg) and naltrexone (0.5μg) produced a greater reduction of melatonin-induced spinal antiallodynia than individual antagonists (Fig. 6b).
Effect of intrathecal 4P-PDOT (a) or the combination of 4P-PDOT and naltrexone (b) naltrexone on oral and spinal melatonin-induced antiallodynic activity, respectively, in rats submitted to ligation of L5/L6 spinal nerves. Rats were treated with vehicle or naltrexone (−40 min) and melatonin (−30 min) before starting threshold evaluations. Data are expressed as the area under the 50% withdrawal threshold against time curve (AUC). Bars are the mean ± SEM for six animals. ∗ Significantly different from the melatonin group, as determined by one-way ANOVA followed by the Tukey’s test.
3.6. Effect of melatonin on motor co-ordination test
Animals did not have a fall from the rotarod test before administration of either systemic or intrathecal melatonin (Table 1). Oral (300mg/kg) and intrathecal (100μg, it) administration of melatonin produced 1 fall in 1 of 6 rats during the rotarod test (Table 1). Moreover, oral or spinal administration of vehicle showed the same pattern (Table 1). Statistical analysis (Kruskal–Wallis) did not show a significant difference in falls after melatonin administration compared to vehicle, thus suggesting that this drug does not have effects on motor co-ordination in the rats at 45min after treatment.
Effect of melatonin on motor coordination in the rats
4. Discussion
4.1. Systemic and intrathecal antiallodynic effect of melatonin
In this study, we have shown that systemic (oral) and intrathecal administration of melatonin is able to reduce tactile allodynia in rats with neuropathic pain. This antiallodynic effect was independent of any motor effect as administration of the greatest systemic dose (300mg/kg) significantly reduced tactile allodynia without affecting co-ordination in the rotarod test, as previously reported (Tu et al., 2004). It has been found that melatonin produces an antinociceptive effect in acute (Lakin et al., 1981; Golombek et al., 1991; Yu et al., 2000a,b; El-Shenawy et al., 2002; Naguib et al., 2003; Dhanaraj et al., 2004) and inflammatory (Cuzzocrea et al., 1997; Raghavendra et al., 2000; Pang et al., 2001; Bilici et al., 2002; El-Shenawy et al., 2002; Ray et al., 2004) pain models after spinal (Noseda et al., 2004; Onal et al., 2004; Tu et al., 2004), supraspinal (Yu et al., 2000b; Ulugol et al., 2006) or systemic (Golombek et al., 1991; Raghavendra et al., 2000; Yu et al., 2000a,b; Ulugol et al., 2006) administration. Thus, we have extended these observations by showing that systemic or intrathecal melatonin significantly reduced L5/L6 spinal nerve ligation-induced tactile allodynia. To our knowledge, this is the first report about the antiallodynic effect of melatonin in a neuropathic pain model. Our results disagree with those of Ulugol et al. (2006) who were not able to observe an antiallodynic effect in sciatic nerve-injured neuropathic mice after systemic and supraspinal administration of melatonin. We have reported an antiallodynic effect for spinal gabapentin, a well-known drug used in patients with neuropathic pain, in this model of neuropathy in rats (Mixcoatl-Zecuatl et al., 2004, 2006), therefore differences between this study and that of Ulugol et al., could be due to the different ways used to induce allodynia. Our results, however, agree with evidence showing that intrathecal administration of melatonin agonists significantly reduces touch-evoked pain (secondary mechanical allodynia) in rats injected with capsaicin (Tu et al., 2004). Our results also agree with data indicating that intrathecal administration of melatonin depresses synaptic potentiation (wind-up) in the spinal cord (Noseda et al., 2004), a process known to play an important role in central sensitization and neuropathic pain (Millan, 1999).
4.2. Effect of luzindole and 4P-PDOT on the oral and intrathecal antiallodynic activity of melatonin
The spinal antiallodynic effect of melatonin was diminished by the intrathecal administration of luzindole. Since luzindole is a preferential MT2 receptor antagonist (Dubocovich et al., 1997; Browning et al., 2000), our data suggest that the melatonin-induced antiallodynia could be due to activation of spinal MT2 receptors. In order to confirm this suggestion, we used the highly selective MT2 receptor antagonist 4P-PDOT (Dubocovich et al., 1997; Browning et al., 2000). Intrathecal administration of 4P-PDOT diminished the antiallodynic effect of melatonin administered intrathecally. Therefore, our data strongly suggest that the melatonin-induced antiallodynic effect observed after intrathecal administration results from activation of spinal MT2 receptors. These results agree with the presence of MT2 receptors in the dorsal horn of the lumbar spinal cord (Pang et al., 1997; Zahn et al., 2003). The data also agree with an inhibitory role for MT2 receptors. In fact, there is evidence that binding of melatonin to MT2 receptors decreases intracellular concentrations of cyclic AMP, Ca2+, diacylglycerol and arachidonic acid in the anterior pituitary of rats (Iuvone and Gan, 1994; Vanecek, 1998). Moreover, recent data suggest that melatonin may induce hyperpolarization by activation of an outward potassium current in rat suprachiasmatic nucleus neurons in vitro (van den Top et al., 2001).
Our data would suggest that endogenous melatonin could arrive, via the blood circulation, at the dorsal horn in order to activate MT2 receptors in this site. Accordingly, there is evidence showing that the hormonal melatonin message delivered by the pineal gland is distributed rapidly via the systemic circulation to all peripheral and central structures where melatonin acts via specific receptors (Simonneaux and Ribelayga, 2003). However, besides the pineal gland, melatonin is reported to be produced in a number of extrapineal sites, including the spinal cord, where it could act as an intracellular mediator or paracrine signal in addition to its endocrine effects (Stefulj et al., 2001). Besides producing an antiallodynic effect after intrathecal application, oral administration of melatonin was also able, although to a lesser extent, to reduce tactile allodynia in neuropathic rats and this antiallodynic effect was significantly blocked by oral administration of 4P-PDOT. These results also suggest the possible participation of MT2 receptors in the antiallodynic effect of systemic melatonin. This effect could result from activation of MT2 receptors located in primary afferent neurons (Ayar et al., 2001) or in the spinal cord (see above). However, the fact that intrathecal treatment with 4P-PDOT is able to diminish remarkably the antiallodynic effect induced by the oral administration of melatonin suggests an important spinal component in the mechanism of action of systemic melatonin.
Although intrathecal administration of 4P-PDOT (1–10μg) and luzindole (10–100μg) was able to block the antiallodynic activity of melatonin, the spinal application of 10μg 4P-PDOT and 100μg luzindole alone in neuropathic rats had no effect on tactile allodynia, which suggests that the spinal endogenous melatonin system does not have a tonic inhibitory role in neuropathic pain in this condition.
4.3. Effect of naltrexone on the oral or intrathecal antiallodynic activity of melatonin
Several studies have found that melatonin-induced antinociception can be attenuated by opioid receptor antagonists (Lakin et al., 1981; Golombek et al., 1991; Yu et al., 2000b). In addition, other observations point to significant interactions between melatonin and opioid peptides (Kumar et al., 1982; Xu et al., 1995; Shavali et al., 2005). In order to assess the possible participation of either opioid receptors or opioid peptides in the melatonin-induced antiallodynia, the effect of naltrexone on the antiallodynic activity of melatonin was assessed. Subcutaneous or intrathecal administration of the non-selective opioid receptor antagonist naltrexone diminished the antiallodynic effect induced by either systemic or spinal administration of melatonin. These results agree with previous observations showing that melatonin-induced systemic antinociception (in glutamate-induced nociception) can be blocked by the intraperitoneal administration of the opioid receptor antagonist naloxone (Mantovani et al., 2006). Since melatonin does not bind to opioid receptors (Shavali et al., 2005), these results suggest that melatonin induces the release of opioid peptides in order to produce its antiallodynic effect in the spinal cord. Accordingly, there are several observations where melatonin induces an increase of β-endorphin in the central nervous system (Shavali et al., 2005). Taken together the data suggest that the melatonin-induced antiallodynic effect may be mediated via the release of β-endorphin. Then, β-endorphin could bind to μ, κ (Tseng et al., 1995) or putative ε opioid receptors in order to produce its effect. However, the fact that the mixture of small intrathecal doses of naltrexone (0.5μg) and 4P-PDOT (0.1μg) produced a greater reduction of melatonin-induced spinal antiallodynia than individual antagonists would suggest that both opioid and MT2 spinal receptors play an important role in the spinal mechanism of action of melatonin in this model.
In conclusion, melatonin reduced tactile allodynia in neuropathic rats. The systemic and spinal antiallodynic effect of melatonin was partially diminished by luzindole and 4P-PDOT as well as by naltrexone. These results suggest that melatonin may activate MT2 and opioid (possibly via the increase in β-endorphin release) receptors, in order to produce its antiallodynic effect in this model of neuropathy.
Acknowledgements
Authors greatly appreciate the technical and bibliographic assistance of Guadalupe C. Vidal-Cantú and Héctor Vázquez, respectively. Mónica Ambriz-Tututi is a CONACYT fellow. This work is part of the M.Sc. dissertation of Mónica Ambriz-Tututi.
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Keywords:
Neuropathic pain; Melatonin; MT2 receptors; β-Endorphins; Spinal processing; Tactile allodynia
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