Therapeutic Perspectives for Melatonin Agonists and Antagonists

Abstract

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.

Night Shift Work and the Risk of Endometrial Cancer

“…Prior studies suggest that melatonin has a role in obesity and energy balance (26). In rodents, melatonin regulates intestinal motility, with a shorter postprandial intestinal motor response during the dark phase than in the light phase: body weight gain was greater in animals kept under short days compared with animals kept under a natural photoperiod (27). In humans, an association between night work and the metabolic syndrome has previously been noted (28).…”

Variations in the Light-induced Suppression of Nocturnal Melatonin with Special Reference to Variations in the Pupillary Light Reflex in Humans

“…In addition, it has been suggested that this hormone may elicit anxiolytic effects (Delagrange et al, 2003), and suppress cancer induction and tumor cell proliferation (Glickman et al, 2002;Dauchy et al, 1999). As such, the effect of lighting on human health is a crucial issue, as high-illuminance light and lighting with a high color temperature during nighttime are irradiated repeatedly on the living system to consistently suppress melatonin secretion (Yasukouchi, 2005;Tsutsumi et al, 2002;Brainard et al, 2001;Morita, 1996).…”

Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase

“…Melatonin is a hormone that regulates multiple physiological functions [1]. It is synthesized in the pineal gland, through a pathway in which the first steps are tryptophan hydroxylation and the subsequent decarboxylation thereof.…”