The analgesic effects of peripheral and central administration of melatonin in rats
Introduction
Melatonin is the main hormone secreted by the pineal gland. It was isolated in 1958 (Lerner et al., 1958). This indole compound (N-acetyl-5-methoxytryptamine) is derived from serotonin after two biochemical steps. It has been implicated in some pharmacological effects including sedative/hypnotic, anticonvulsant activity, etc. Sugden, 1983, Geoffriau et al., 1998. In particular, melatonin administered intraperitoneally (i.p.) has been shown to possess a potent and long-lasting antinociceptive effect in mice and rats, suggesting that it produces analgesia Lakin et al., 1981, Golombek et al., 1991, Yu et al., 1999b.
However, the site and mechanism of action of melatonin to induce analgesia remain to be clarified. Melatonin receptors are found in both the central nervous system (CNS) and peripheral tissues (Vanecek, 1998). Melatonin is known to exert its effects through melatonin receptors. Relatively abundant melatonin receptors are found in several brain regions, particularly the hypothalamus Stankov et al., 1991a, Stankov et al., 1991b, Morgan et al., 1994. Moreover, Pang and Brown (1983) have reported that melatonin in the brain is unevenly distributed, with a high level in the hypothalamus, and that the ratio of its concentration in whole brain to that in serum is about 9:1 during the dark period and 3:1 during the light period in rats. Melatonin can penetrate the blood–brain barrier. Therefore, it is logical to assume that the brain may be one of the most important sites for melatonin to exert an analgesic effect. To clarify this matter, we evaluated the analgesic effects of i.p. and intracerebroventricular (i.c.v.) administration of melatonin in rats. Furthermore, others and we have previously shown that peripheral administration of naloxone may blunt the analgesic effect induced by melatonin Lakin et al., 1981, Golombek et al., 1991, Yu et al., 1999b. Several observations point to a significant interaction between melatonin and opioid peptides in the brain Kumar et al., 1982, Xu et al., 1995. It was of interest to determine whether melatonin-induced analgesia was related to the central opioid system. The present study investigated the effect of i.c.v. naloxone on melatonin-induced analgesia.
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Animals
Experiments were performed on male Sprague–Dawley rats weighing 180–230 g which were supplied by the Experimental Animal Center, Shanghai Medical University, China. The animals were housed in groups of four, with free access to standard rat diet and tap water in a room with 12:12 h light/dark cycle (lights on from 08:00 to 20:00 h). Each rat was used in one experiment only. All the protocols in the present study were approved by the local ethics committee in Shanghai, China.
Drugs
Melatonin was
Antinociceptive effects of i.p. melatonin
The mean baselines of tail flick latency in the four groups of rats (n=8, each) were 6.12±0.38, 5.91±0.52, 5.88±0.57 and 5.72±0.47 s, respectively. There were no significant differences (P>0.05) between the mean baselines of tail flick latency in the vehicle-treated and melatonin-treated rats. As shown in Fig. 1, melatonin produced dose-dependent antinociception following its i.p. administration. In the groups with larger doses (60 and 120 mg/kg), the effective antinociception started 15 min
Discussion
A number of behavioral studies have shown that melatonin administered peripherally exerts an antinociceptive action against thermal and chemical stimuli in mice Lakin et al., 1981, Sugden, 1983, Golombek et al., 1991. We have also observed (Yu et al., 1999b) that the i.p. injection of melatonin resulted in dose-dependent antinociception in rats and mice in a nociceptive test, electrical stimulation vocalization. In the present study, a similar antinociceptive effect induced by i.p.
Acknowledgements
This work was financially supported by the Natural Science Foundation of Fujian Province of China (No. C96038) and the Key Project for the Ninth Five-year Plan of China (No. 96-906-11-01).
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