Melanoma is a leading cause of cancer deaths worldwide. Although immunotherapy has revolutionised the treatment for some patients, resistance towards therapy and unwanted side effects remain a problem for numerous individuals. Broad anti-cancer activities of melatonin are recognised, however additional investigations still need to be elucidated. Herein, using various human melanoma cell models, we explore in vitro the new insights into the regulation of melanoma by melatonin and its metabolites which possess, on the other side, high safety profiles and biological meaningful. In this study, using melanotic (M<em>N</em>T-1) and amelanotic (A37<em>5</em>, G361, Sk-Mel-28) melanoma cell lines, the comparative oncostatic responses, the impact on melanin content (for melanotic M<em>N</em>T-1 melanoma cells) as well as the mitochondrial function controlled by melatonin, its precursor (serotonin), a kynuric (<em>N</em>¹ -<em>acetyl</em>-<em>N</em>² -formyl-<em>5</em>-methoxykynuramine, AFMK) and indolic pathway (6-hydroxymelatonin, 6(OH)MEL and <em>5</em>-<em>methoxytryptamine</em>, <em>5</em>-MT) metabolites were assessed. <em>N</em>amely, significant disturbances were observed in bioenergetics as follows: (i) uncoupling of oxidative phosphorylation (OXPHOS), (ii) attenuation of glycolysis, (iii) dissipation of mitochondrial transmembrane potential (mtΔΨ) accompanied by (iv) massive generation of reactive oxygen species (ROS), and (v) decrease of glucose uptake. Collectively, these results together with previously published reports provide a new biological potential and make an imperative to consider using melatonin or its metabolites for complementary future treatments of melanoma-affected patients, however these associations should be additionally investigated in clinical setting.

Keywords: extracellular acidification rate; glucose uptake; melanoma cells; metabolites of melatonin; mitochondrial function; oxygen consumption rate; transmission electron microscopy.

Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in clinical radiobiology. However, resistance to radiotherapy for colorectal cancer greatly decreases the therapeutic outcome. Melatonin (<i><em>N</em></i>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a natural secretory product that the pineal gland in the brain normally produces, has been reported to have anticancer properties. In the study, we investigated the combination of melatonin with radiotherapy as a treatment for colorectal cancer. We firstly explored the anti-tumor activity of melatonin combined with ionizing radiation (IR) against colorectal carcinoma in vitro. It was found that melatonin effectively inhibited human colorectal carcinoma cell line HCT 116 cellular proliferation, colony formation rate and cell migration counts following IR. Increasing the radiosensitivity of colorectal cancer cells by melatonin treatment was found to be associated with cell cycle arrest in the G2/M phase, downregulation of proteins involved in D<em>N</em>A double-strand break repair and activation of the caspase-dependent apoptotic pathway. Moreover, we also investigated the combined effect of IR and melatonin on colorectal tumor in vivo. Results from a tumor xenograft showed that melatonin plus IR treatment significantly suppressed tumor cell growth compared with melatonin or IR alone, resulting in a much higher tumor inhibition rate for the combined treatment. The data suggested that melatonin combined with IR could improve the radiosensitivity of colorectal cancer and thus enhance the therapeutic effect of the patients, implying melatonin could function as a potential sensitizer in tumor radiotherapy.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MEL) is a hormone produced by the pineal gland that was discovered many years ago. The physiological roles of this hormone in the body are varied. The beneficial effects of MEL administration may be related to its influence on mitochondrial physiology. Mitochondrial dysfunction is considered an important factor in various physiological and pathological processes, such as the development of neurodegenerative and cardiovascular diseases, diabetes, various forms of liver disease, skeletal muscle disorders, and aging. Mitochondrial dysfunction induces an increase in the permeability of the inner membrane, which leads to the formation of a permeability transition pore (mPTP) in the mitochondria. The long-term administration of MEL has been shown to improve the functional state of mitochondria and inhibit the opening of the mPTP during aging. It is known that MEL is able to suppress the initiation, progression, angiogenesis, and metastasis of cancer as well as the sensitization of malignant cells to conventional chemotherapy and radiation therapy. This review summarizes the studies carried out by our group on the combined effect of MEL with chemotherapeutic agents (retinoic acid, cytarabine, and navitoclax) on the HL-60 cells used as a model of acute promyelocytic leukemia. Data on the effects of MEL on oxidative stress, aging, and heart failure are also reported.

Keywords: aging; cancer; heart failure; melatonin; mitochondrial dysfunction; oxidative stress.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a naturally occurring small molecule, can protect plants against abiotic stress after exogenous treatmenting with it. It is not known if melatonin homologs, such as <em>5</em>-<em>methoxytryptamine</em> and <em>5</em>-methoxyindole, that are easy and more cost-effective to synthesize can stimulate the plant immune system in the same manner as melatonin. In the present study, we assessed the biological activity of the melatonin homologs, <em>5</em>-methoxytryptamin and <em>5</em>-methoxyindole. The results showed that melatonin and its homologs all induced disease resistance against <i>Phytophthora nicotianae</i> in <i><em>N</em>icotiana benthamiana</i> plants. The application of all three compounds also induced stomatal closure and the production of reactive oxygen species. Gene expression analysis indicated that the expression of genes involved in hydrogen peroxide (H₂O₂), nitric oxide (<em>N</em>O) production, and salicylic acid (SA) biosynthesis was significantly upregulated by all three compounds. Four homologs of the melatonin receptors were identified by blasting search with the phytomelatonin receptor in <i>Arabidopsis</i>. Molecular docking studies were also used to identify four putative melatonin receptors in <i><em>N</em>. benthamiana</i>. Further experimentation revealed that silencing of the melatonin receptors trP47363 and trP13076 in <i><em>N</em>. benthamiana</i> compromised the induction of stomatal closure, <i>PR-1a</i> gene expression and SA accumulation by all three compounds. Collectively, our data indicate that the induction of defense responses in <i><em>N</em>. benthamiana</i> by melatonin, <em>5</em>-<em>methoxytryptamine</em>, and <em>5</em>-methoxyindole involves the melatonin receptors trP47363 and trP13076.

<strong class="sub-title"> Keywords: </strong> <em>5</em>-methoxyindole; <em>5</em>-methoxytryptamin; <em>N</em>icotiana benthamiana; disease resistance; melatonin; salicylic acid; stomatal closure; transmembrane receptor.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an evolutionary highly conserved molecule that plays an important role in conveying the clock and calendar information to all living organisms, including man. The hormone is synthesized mainly by the pineal gland, and, to a lesser extent, by extrapineal tissues--such as the retina, Harderian gland, and gastrointestinal tract. The melatonin-generating system is characterized by three basic features: (1) photosensitivity, (2) diurnal (or circadian) rhythmicity (with highest levels of the hormone production occurring at night in darkness), and (3) age-related decrease in its activity. This review surveys data on the regulation of rhythmic melatonin biosynthesis by an array of factors, such as circadian pacemaker, light, neurotransmitters, second and third messenger molecules. Recent developments in the field of melatonin receptors are also presented. Finally, physiological and therapeutic properties of melatonin, with a special emphasis given to possible applications of this compound in the treatment of circadian rhythm sleep disorders, are discussed.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a well-known animal hormone, is involved in several biological processes including circadian rhythm and the regulation of abiotic stress. A systematic understanding of the circadian regulation of melatonin biosynthesis-related genes has not been achieved in rice. In this study, key genes for all of the enzymes in the melatonin biosynthetic pathway that showed a peak of expression at night were identified by microarray data analysis and confirmed by qRT-PCR analysis. We further examined the expression patterns of the four genes under drought, salt, and cold stresses. The results showed that abiotic stresses, such as drought, salt, and cold, affected the expression patterns of melatonin biosynthetic genes. In addition, the circadian expression patterns of tryptophan decarboxylase (<i>TDC</i>), tryptamine <em>5</em>-hydroxylase (<i>T<em>5</em>H</i>), and serotonin <i><em>N</em></i>-<em>acetyl</em>transferase (<i>S<em>N</em>AT</i>) genes in wild-type (WT) plants was damaged by the drought treatment under light and dark conditions. Conversely, <i><em>N</em></i>-<em>acetyl</em>serotonin <i>O</i>-methyltransferase (<i>ASMT</i>) retained the circadian rhythm. The expression of <i>ASMT</i> was down-regulated by the rice <i>gigantea</i> (<i>OsGI</i>) mutation, suggesting the involvement of the melatonin biosynthetic pathway in the OsGI-mediated circadian regulation pathway. Taken together, our results provide clues to explain the relationship between circadian rhythms and abiotic stresses in the process of melatonin biosynthesis in rice.

Keywords: abiotic stress; circadian rhythm; gene expression; melatonin biosynthesis; rice.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MT) is a hormone synthesized and secreted by the pineal gland. Recent studies show that melatonin plays an essential role in the pathogenesis of many reproductive processes. High-concentration melatonin exists in human preovulatory follicular fluid and melatonin receptors are present in ovarian granulosa cells, which indicates the direct effects of melatonin on ovarian function. Reactive oxygen species are involved in a number of reproductive events, including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum formation. Melatonin and its metabolites, as powerful antioxidants and free radical scavengers, can potentially inhibit premature ovarian failure. Literature published in recent years shows the essential roles of melatonin in improving human ovarian function and oocyte quality as well as in the management of infertility. Researches on the action mechanisms of melatonin may provide a theoretical basis for the prevention and treatment of some clinical diseases.

Melatonin or <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> is mainly produced by pineal gland and exhibits characteristic diurnal rhythm of synthesis and secretion with the highest levels at night and low levels during a day. For several years the knowledge of pineal gland and its hormone was rather poor. It was last years when knowledge of the role of melatonin in health and different diseases was developed. <em>N</em>owadays we are aware that melatonin plays important role in diagnosis and therapy of several diseases, and may be helpful factor also in neurosurgery. Author presents the review of the present knowledge on the role of melatonin in diagnosis of pineal region pathology and treatment of brain tumors.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) plays important roles in the regulation of development and the response to biotic and abiotic stresses in plants. Serotonin-<em>N</em>-<em>acetyl</em>transferase (S<em>N</em>AT) functions as a key catalytic enzyme involved in melatonin biosynthesis. In this study, the candidate gene VvS<em>N</em>AT1 (S<em>N</em>AT isogene) was isolated from grape (Vitis vinifera L. cv. Merlot). Tissue-specific expression and external treatment revealed that VvS<em>N</em>AT1 is a salt-inducible gene that is highly expressed in leaves. Subcellular localisation results revealed that VvS<em>N</em>AT1 was located in the chloroplasts, which is similar to other plant S<em>N</em>AT proteins. Ectopic overexpression of VvS<em>N</em>AT1 in Arabidopsis resulted in increased melatonin production and salt tolerance. Transgenic Arabidopsis overexpressing VvS<em>N</em>AT1 exhibited enhanced growth and physiological performance, including a lower degree of leaf wilting, higher germination rate, higher fresh weight, and longer root length under salt stress. Moreover, overexpression of VvS<em>N</em>AT1 in Arabidopsis protected cells from oxidative damage by reducing the accumulation of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂). These results indicate that VvS<em>N</em>AT1 positively responds to salt stress. Our results provide a novel perspective for VvS<em>N</em>AT1 to improve salt tolerance, mediated by melatonin accumulation, plant growth promotion and oxidative damage reduction.

Keywords: Melatonin; Salt stress; Transgenic Arabidopsis; Vitis vinifera; VvSNAT1.

The pineal hormone melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) exerts antigonadotropic effects in some mammalian species. To evaluate the effect of luteinizing hormone (LH) on melatonin release and its synthesizing enzyme activities in pineal glands, pineals of adult female rats undergoing diestrus were organ-cultured in a medium containing 10(-12), 10(-10) or 10(-8) M LH for 6 h. Melatonin release increased significantly in pineals cultured with 10(-12) and 10(-10) M LH, as compared to control values. Similarly, the activity of arylalkylamine <em>N</em>-<em>acetyl</em>transferase (<em>N</em>AT), the key regulatory enzyme in melatonin biosynthesis, was significantly higher in pineals cultured with 10(-12) and 10(-10) M LH for 6 h, while LH at 10(-8) M had no effect. Although LH at 10(-10) M increased pineal hydroxyindole-O-methyltransferase (HIOMT) activity, which catalyzes the final step of melatonin biosynthesis, LH at 10(-12) and 10(-8) M had no effect. These results demonstrate that at relatively low physiological levels, LH stimulates pineal melatonin synthesis and release, mainly by increasing <em>N</em>AT activity.

Melatonin receptor sites were characterized in the brains of four avian species (duck, goose, pigeon, and turkey) by an in vitro binding technique, using 2-[12<em>5</em>I]iodomelatonin as a labeled ligand. The specific binding of 2-[12<em>5</em>I]iodomelatonin to avian brain membranes was found to be stable, saturable, reversible, and of high affinity. Scatchard analysis revealed that 2-[12<em>5</em>I]iodomelatonin binds to a single class of sites in brain membrane preparations of these species with high affinity (affinity constants Kd between 1<em>5</em>3 and 289 pM) and low capacity (total number of binding sites B(max) between <em>5</em>.07 and 10.1<em>5</em> fmol/mg protein). Competition studies showed the following relative order of potency of indolic compounds to inhibit the specific 2-[12<em>5</em>I]iodomelatonin binding: melatonin>>) <em>N</em>-<em>acetyl</em>tryptamine>> <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptamine>> <em>5</em>-hydroxytryptamine>>>> <em>5</em>-<em>methoxytryptamine</em>. We conclude that the 2-[12<em>5</em>I]iodomelatonin-binding sites in brains of duck, goose, pigeon, and turkey have similar binding and pharmacological characteristics, and may represent ML-1 melatonin receptor sites.

Synthetic melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MT) is popular in the US and Asian markets as a health supplement. Here, we identified a naturally occurring melatonin source in apple juice. Melatonin was present in all 18 apple cultivars tested. The highest melatonin level of the edible part of apple was detected in the apple peel. The melatonin content in 'Fuji' apple juice is comparable to the level of its flesh. Melatonin was consumed during the process of juicing due to its interaction with the oxidants. Melatonin addition significantly reduced the juice color change to brown (browning). The mechanism is that melatonin scavenges the free radicals, which was indicated by the ASBT analysis; therefore, inhibiting the conversion of o-diphenolic compounds into quinones. Most importantly, melatonin exhibited powerful anti-microorganism activity in juice. The exact mechanisms of this action are currently unknown. These effects of melatonin can preserve the quality and prolong the shelf life of apple juice. The results provide valuable information regarding commerciall apple juice processing and storage.

Melatonin or <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, the fascinating molecule secreted by the pineal gland. Melatonin has a close interaction with hypothalamic-pituitary-gonadal axis. In non-seasonal breeders like rat its exact role in reproduction is controvertible. So it is worth to explore the possible role of melatonin on the onset of puberty in male albino rats. Two groups of male rats aged <em>5</em> and 10 days were used for the study. In each group, there were three subgroups, each receiving melatonin for <em>5</em> days, 10 days or till the day of descent of testes. Similar subgroups were used as controls. Without handling, animals were observed daily for the onset of puberty. On the day of descent of testes, body weight of the animal was noted, blood was collected, serum was separated and used for radio immunoassay. For histomorphometric analysis, all morphometric measurements were done using an occular micrometer. Volume fraction of seminiferous tubules, intertubular connective tissue of testes, cortex and medulla of thymus were estimated by point count method. In both the age groups melatonin advanced the age on descent of testes, increased the body weight, organ weight. It also increased the serum hormone levels. So, in conclusion this study indicates that exogenous melatonin advances the onset of puberty in male albino wistar rats and this effect is more pronounced in the younger animals.

To evaluate the effect of gonadotropin-releasing hormone (GnRH) on melatonin ( <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) release and its synthesizing enzyme activities in pineal glands, pineals from adult female rats during diestrus were organ-cultured in a medium containing 10 -12, 10 -10, or 10 -8 M GnRH for 6 h. Melatonin release increased significantly in pineals cultured with 10 -10 and 10 -8 M GnRH compared to controls. However, in pineal glands that were organ-cultured in a medium containing 10 -12 to 10 -8 M GnRH, the activity of arylalkylamine <em>N</em>-<em>acetyl</em>transferase, which is the key regulatory enzyme in melatonin biosynthesis, showed no significant difference from controls. Likewise, GnRH at these concentrations had no significant effect on the activity of pineal hydroxyindole- O-methyltransferase, which catalyzes the final step of melatonin biosynthesis. These results show that GnRH stimulates pineal melatonin release, but suggest that GnRH does not affect its melatonin synthesis.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em> <em>methoxytryptamine</em>) is a low molecular weight antioxidant and is an endogeneous defense system against the deleterious actions of the extremely reactive hydroxyl radical. Among the enzymes that participate in the antioxidant functions is cytochrome P-4<em>5</em>0, a stalwart of the detoxification system in the body. Our results revealed that tin-protoporphyrin administration brought about a marked decline in cytochrome P-4<em>5</em>0 levels. This decline was, however, reversed by the coadministration of the antioxidant, melatonin. Thus, the enhanced antioxidant status in melatonin-treated rats may act as a protective mediator of various pharmacological functions altered during tin-protoporphyrin (an antihyperbilirubemenic agent) administration to Wistar rats.

In in vitro study of the human euthyroid and thyrotoxic thyroid gland melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) and, to a lesser measure mexamine (<em>5</em>-<em>methoxytryptamine</em>) had a dose-dependent inhibiting effect on thyroxine secretion. Moreover, melatonin weakened the TSH stimulating effect in relation to the secretory process in the thymus while mexamine did not. Despite the similarity in the quality of the effect of both methoxyindoles on the release of thyroxine, the mechanism of its realization differs: the action of melatonin is mediated by the adenylate-cyclase-cAMP system, but in the action of mexamine the cAMP-dependent mechanism does not take part. Maintenance of the sensibility of the human thyroid to the effect of TSH is an obligatory condition for realization of the action of both methoxyindoles on the secretory process in it.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), the main product of pineal gland in vertebrates, is well known for its multifunctional role which has great influences on the reproductive system. Recent studies documented that melatonin is a powerful free radical scavenger that affects the reproductive system function and female infertility by MT1 and MT2 receptors. Furthermore, cancer researches indicate the influence of melatonin on the modulation of tumor cell signaling pathways resulting in growth inhibitor of the both in vivo/in vitro models. Cancer adjuvant therapy can also benefit from melatonin through therapeutic impact and decreasing the side effects of radiation and chemotherapy. This article reviews the scientific evidence about the influence of melatonin and its mechanism of action on the fertility potential, physiological alteration, and anticancer efficacy, during experimental and clinical studies.

Keywords: Cancer; Female; Fertility; Melatonin.

<strong class="sub-title"> Background: </strong> Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a significant indoleamine neuromodulator implicated in circadian rhythms and sleep patterns, regulates diverse rhythmic functions via activating its high-affinity G-protein-coupled receptors. However, the detailed cellular expression of the Mel1a receptor in the retina is still a research gap.

Methods: The expression of the Mel1a receptor in pigeon retina was assessed using Western blot analysis and immunofluorescent staining. The cellular localization of the Mel1a receptor was studied using double immunofluorescent staining and laser-scanning confocal microscopy.

Results: Our data suggested that the Mel1a receptor was extensively expressed in the outer segment of Rho4D2-labeled rod and L/M-opsin-labeled red/green cone and in the somata of the CB-labeled horizontal cell, TH-labeled dopaminergic amacrine cell, ChAT-labeled cholinergic amacrine cell, PV-labeled AII amacrine cell, Brn3a-labeled conventional ganglion cell, melanopsin-containing ganglion cell and CRALBP-labeled Müller glial cell. In addition, the Mel1a receptor was diffusely distributed throughout the full thickness of the inner plexiform layer. However, the outer segment of S-opsin-labeled blue cone, the somata of ChX-10-labeled bipolar cell and outer plexiform layer seemed to lack immunoreactivity of the Mel1a receptor.

Conclusion: The finding that multiple types of retinal cells express the Mel1a receptor provides a new neurobiological basis for the participation of melatonin in the regulation of retinal functions through activating the Mel1a receptor.

Keywords: cellular localization; circadian rhythm; diurnal animal; retinal Mel1a receptor.

Hepatic ischemia-reperfusion (HIR) injury is a common pathophysiological process in many clinical settings. This study was designed to compare the protective role of octreotide (somatostatin analogue, OCT) and melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MLT) through the modulation of autophagy against HIR injury in rats. Male albino rats were divided into sham, HIR, OCT at three doses (<em>5</em>0, 7<em>5</em>, and 100 μg/kg), MLT, MLT+OCT7<em>5</em>, compound C (AMPK inhibitor, CC), and CC+OCT7<em>5</em> groups. Ischemia was induced for 30 min followed by 24 h reperfusion. Biochemical, histopathological, immunohistochemical, lipid peroxidation, ELISA, qPCR, and western blot techniques were performed in our study. Liver autophagy was restored by OCT at doses (<em>5</em>0 or 7<em>5</em> μg/kg) as indicated by elevating the expressions of Beclin-1, ATG7, and LC3 accompanied by the reduction of p62 expression through induction of AMPK/S317-ULK1 and inhibition of PI3K/AKT/mTOR/S7<em>5</em>7-ULK1 signaling pathways. As well, OCT maintained the integrity of the Keap1-<em>N</em>rf2 system for the normal hepatic functions via controlling the Keap1 turnover through autophagy in a p62-dependent manner, resulting in upholding a series of anti-oxidant and anti-inflammatory cascades. These effects were abolished by compound C. On the other hand, MLT showed a decrease in the autophagy markers via inhibiting AMPK/pS317-ULK1 and activating PI3K/AKT/mTOR/pS7<em>5</em>7-ULK1 pathways. Autophagy inhibition with MLT markedly reversed the hepatoprotective effects of OCT7<em>5</em> after HIR injury. Finally, our results proved for the first time that OCT7<em>5</em> was more effective than MLT as it was sufficient to induce protective autophagy in our HIR model, which led to the induction of <em>N</em>rf2-dependent AMPK/autophagy pathways.

Keywords: AMPK; Nrf2; Octreotide; autophagy; hepatic ischemia-reperfusion; melatonin.

<em>5</em>-<em>Methoxytryptamine</em> and L-tryptophan methyl ester were acylated with malonic acid, dimethyl malonate, or succinic anhydride to produce the corresponding <em>N</em>,<em>N</em>'-dicarbonyltryptamine derivatives. The analgesic activity was evaluated by the tail flick test. All of the compounds exhibited desirable analgesic potency. This result is consistent with that of <em>N</em>-(<em>N</em>-<em>acetyl</em>-L-tryptophanyl)-<em>5</em>-<em>methoxytryptamine</em> and confirmed that introducing substituted tryptamine into the amide chain of melatonin does enhance analgesic potency.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a hormone produced by the pineal gland in the brain in response to darkness. Melatonin is made available when tryptophan is converted to serotonin and then enzymatically converted to melatonin in the pineal gland. Serum levels are low during the day, with peak levels occurring from 2-4 am.

Pineal function was studied in Wistar pubertal male rats in summer and winter. It was demonstrated that the pineal weight is inversely related to the day length, increasing in winter and reducing in summer. In winter pineal serotonin is actively metabolized via <em>N</em>-<em>acetyl</em>ation and subsequent ortho-methylation to form <em>N</em>-<em>acetyl</em> serotonin and melatonin as well as via oxidative deamination followed by ortho-methylation to form <em>5</em>-hydroxyindolacetic and <em>5</em>-methoxyindolacetic acids. In summer serotonin metabolism in the pinealocytes changes to direct ortho-methylation of serotonin to form <em>5</em>-<em>methoxytryptamine</em>. The decreased level of <em>N</em>-<em>acetyl</em>transferase limits the formation of melatonin in the pineal gland in summer.

Melatonin synthesis is controlled by aralkylamine <em>N</em>-<em>acetyl</em>transferase (AA<em>N</em>AT: EC 2.3.1.87) <em>acetyl</em>ating serotonin (<em>5</em>-hydroxytryptamine; <em>5</em>-HT) to <em>N</em>-<em>acetyl</em>serotonin (<em>N</em>AS), and <em>N</em>-<em>acetyl</em>serotonin O-methyltransferase (ASMT: EC 2.1.1.4) methylating <em>N</em>AS to melatonin (Mel; <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>). We examined the levels of expression of the aanat and asmt genes, Mel concentrations as well as AA<em>N</em>AT isozyme activity in the eyeball (with retina) and skin of the three-spined stickleback (Gasterosteus aculeatus), at noon and midnight. We found mR<em>N</em>A of four genes (aanat1a, snat, asmt and asmt2) in the eyeball, and two (aanat1a and asmt2) in the skin. The presence of two transcripts of genes encoding AA<em>N</em>AT and two of ASMT in the eyeball at noon and midnight, suggests activity of AA<em>N</em>AT and ASMT isozymes in metabolic pathways besides "the way to melatonin", all the more so because day/night changes in Mel concentration do not follow the changes in either the expression of genes or the activity of AA<em>N</em>AT. The high effectiveness of noon <em>N</em>AS synthesis in the eyeball at low substrate concentrations, which is not reflected in high Mel production, suggests the function of eye <em>N</em>AS beyond that of a precursor to the biosynthesis of Mel. The inhibition of AA<em>N</em>AT isozyme activity by product observed in the eyeball may be one of the mechanisms of <em>5</em>-HT husbanding in the eye (retina). The presence of transcripts of genes encoding both AA<em>N</em>AT and ASMT and the activity of AA<em>N</em>AT, at noon and midnight, supports a local Mel synthesis in the sticklebacks' skin.