Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies

A new horizon into the pathobiology, etiology and treatment of migraine.

Sexual dimorphism in the prevalence of migraine (70% women 30% men) suggests the involvement of reproductive hormones in a women's life. Excessive estrogen during menstruation directly stimulate estrogen receptor alpha thickly populated in trigeminal ganglia and periaqueductal gray which manifest as menstrual migraine. In contrast increased progesterone during pregnancy evokes progesterone receptors A/B, which coexist with ERs, providing complete remission from migraine episodes. Moreover, estrogen also increases nociception through extracellularly signal-regulated kinase (ERK) stimulation and down-regulating antinociceptive GABA, IL-R1 and Zn-fingers. Hormones may provoke migraine indirectly by disrupting mineral homeostasis. Estrogen enhances the absorption and half-life of copper which in turn inhibits the absorption of zinc. Zinc is required for the synthesis of melatonin and CoQ10 essential for growing women. Excess of copper exacerbates the deficiency of zinc, melatonin and CoQ10 typically low in migraineurs. Melatonin is an antioxidant, free radical scavenger and activates antioxidant enzymes like CuZn-superoxide dismutase, catalase, glutathione peroxidase (a Se-enzyme) and glutathione reductase. Zinc deficiency reduces activity of CuZn-SOD. Magnesium and vitamin B6 modulates the level of NO in the cell, both of which are deficient in migraineurs. Magnesium is essential for the removal of trapped NO from within the cell which does not occur under low magnesium levels, which reacts with superoxide generating dangerous peroxynitrite. Iron stimulates nitric oxide synthase producing more NO which is inhibited by zinc, thus, antagonizing peroxynitrite generation. Female hormones lowers magnesium but increase calcium levels which enhance migraine ubiquitousness. Accumulation of copper and iron in deep areas of brain and peripheral nerves typically catalyses the oxidation of catecholamines and generate free radicals involved in lipid-peroxidation, demyelination, denudation of axons and neurodegeneration in specific areas exposing hyperalgesic axons provoking Classical migraine. Furthermore, zinc is an essential component of Zn-fingers (Krox20 and Krox24) which play a pivotal role in the differentiation of Schwann cells-the mainstay for the myelination/remyelination of peripheral nerves. Taken together, conceptually and logically, 30 migraineurs were administered 75 mg of zinc sulfate orally in water daily for 6 weeks+one capsule of vitamin B-complex+one capsule of vitamin A or E (first 10 days) which almost cured all of them. Placebo controlled trials with incremental doses of zinc sulfate along with magnesium and selenium are proposed to augment recovery involving large population of migraineurs. Monitoring of hair and blood mineral analysis for rational therapy is recommended.