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Progress in understanding the pathogenesis underlying migraine has been made with the identification of signaling molecules that are involved in the genesis of a migraine attack. This advance has facilitated the development of mechanism-based therapies for migraine. In my presentation I will review the current understanding of the pathogenesis of migraine, which is based predominantly on clinical data published within the past 10 years, and outline recommended practices for the treatment of acute migraine and for preventive treatment of migraine, emphasizing medications that have recently been approved.

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The purpose of this study was to determine the effects of BoNT-A/atogepant (ATO) combination treatment on activation/sensitization of high-threshold (HT) and wide-dynamic range (WDR) trigeminovascular neurons in the spinal trigeminal nucleus (STN) by CSD. ATO is a small molecule CGRP receptor antagonist.

(A) Individual analysis: in the control group, CSD activated 80% of HT and 70% of WDR neurons whereas in the treatment group it activated 10% of HT (p= .001, c²= 9.8) and 0% of WDR (p= .001, c²= 10.7) neurons. Similarly, in the control group, CSD sensitized 80% of HT and 60% of WDR neurons whereas in the treatment group it sensitized 0% of HT and 5% of WDR neurons. (B) Group analysis: statistical analyses of all neurons revealed that in the control group, spontaneous activity increased significantly in both HT (c²= 6.4, p= 0.039) and WDR (c²= 7.8, p= 0.004) neurons, whereas in the treatment group it remained unchanged in the HT (c²= 1.4, p= 0.35) and decreased, rather than increased, significantly (c²= 8.6, p= 0.003) in the WDR neurons. A similar pattern was seen in responses to mechanical stimulation of the dura and skin.

Given BoNT-A preferential inhibitory effects on unmyelinated C- but not thinly myelinated Ad-fibers, and fremanezumab preferential inhibitory effects on Ad- but not C-fibers, it is reasonable to propose that the robust inhibition of activation and sensitization of the HT and WDR trigeminovascular neurons by the BoNT-A/ATO combination treatment was achieved through a dual blockade of both classes of meningeal nociceptors.

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The hypothalamus plays a critical role in regulating the body homeostasis. This area of the brain works by setting the values of set point, integrates metabolic input information and adjusts the output control via the autonomic and endocrine systems. The endocannabinoid system is composed of cannabinoid receptor types 1 and 2 (CB1 and CB2) and two major endogenous ligands, N-arachidonyl ethanolamine (anandamide) and 2-arachidonoyl glycerol, have been found to exert pronounced regulatory effects on hypothalamic neuroendocrine functions especially those controlling feeding behavior, sleep and stress response. The endocannabinoids, as a retrograde messenger, activate presynaptic CB1 receptors, leading to decreased release of other neurotransmitters such as GABA and glutamate. In the hypothalamus, endocannabinoids reduce GABA release and disinhibit melanocortin-concentrating hormone neurons, leading to an increase in food intake. The orexigenic effect of endocannabinoids is also mediated via modulating the release of other neurotransmitters including neuropeptide Y, melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript and ghrelin. Endocannabinoid system modulates the activity of hypothalamic-pituitary-adrenocortical axis under both basal and stress-related conditions. Presynaptic CB1 receptor signaling regulates the release of corticotropin-releasing hormone from hypothalamic paraventricular neurons and plays a role in stress response. Endocannabinoids also promote rapid-eye-movement sleep by interacting with melanin-concentrating hormone neurons in the lateral hypothalamus. Based on these effects, endocannabinoids have potential therapeutic benefit for several conditions. On the other hand, dysfunction of this system could be involved in the development of several psychiatric disorders.