Effect of melatonin on the control of cerebrovascular nociceptive system

Abstract

Clinical evidences show the inverse relationship between migraine attack and sleep. Melatonin, a pineal hormone which mainly being produced at night, has been hypothesized to involve in migraine pathophysiology. Several biological effect of melatonin, i.e. vasoconstriction, pain modulation, antioxidant, etc. imply its potential benefit in migraine prevention. Its nocturnal surge may play a role in inhibiting the development of migraine during sleep period. This study was conducted to investigate the effects of melatonin in controlling the trigeminovascular nociceptive system. Adult male Wister rats weighing 250-300 g was divided into multiple groups of five rats. Two experimental models for migraine, namely cortical spreading depression (CSD) and nitric oxide-donor (nitroglycerine, GTN) infusion models were chosen in this study. CSD was induced by topical application of three milligram of solid potassium chloride on frontal cortex. Melatonin was given(30 milligram intravenously) prior to CSD induction or NTG infusion. Cerebral microcirculation was assessed using laser Doppler flowmetry (LDF) and intravital fluorescent videomicroscopy. Ultrastructure of cerebral microvessels was studied using electron microscopy. Trigeminal nociception was determined by the expression of c-fos in trigeminal nucleus caudalis (TNC). Expression of nitric oxide synthase (NOS) enzyme in TNC was studied using immunohistochemical method. The results demonstrated that topical and systemic administration of melatonin resulted in the immediate cortical vasoconstriction. Pretreatment with melatonin showed strong attenuation effect on CSD-evoked cortical hyperemia. Melatonin also inhibited NTG-induced pial microvascular dilation. Our electron microscopic study revealed that pretreatment with melatonin could minimize the effect of GTN in induction of microvilli formation and pinocytosis in cortical endothelial cells. These changes in the vascular compartment were parallel to the changes in neural compartment. Reduction of CSD-evoked Fos immunoreactive in TNC neurons was evident in melatonin pretreated group reflecting the attenuation of trigeminal nociceptive activation. The same result was observed in nitric oxide-donor infusion model. Melatonin also minimized the effect of CSD and GTN on inducing NOS expression. These findings revealed the potential anti-migraine effect of melatonin in two models. It also indicated that such effect of melatonin is mediated via the modulation of both vascular and neuronal compartments of trigeminovascular system.