Medication overuse headache is estimated to affect 2% of the population, and is ranked in the top 20 most disabling disorders due to its high level of disability. Several therapies used in the treatment of acute migraine are thought to be associated with medication overuse headache, including opioids and triptans. With limited treatment options, it is critical to determine the risk profile of novel therapies prior to their widespread use. The current study explores the potential medication overuse risk of two novel therapeutic drug classes, namely the ditans: 5-HT1F receptor agonists, and the gepants: calcitonin gene-related peptide receptor antagonists, in a preclinical model of medication overuse. Persistent exposure of mice to the 5-HT1F agonist LY344864, but not olcegepant produced a significant reduction in hind paw and orofacial mechanical withdrawal thresholds as a surrogate readout of allodynia. In agreement, only LY344864 induced neuroplastic changes in trigeminal sensory afferents, increasing calcitonin gene-related peptide expression and basal trigeminal nociception. Our data highlight a differential medication overuse headache risk profile for the ditan and gepant classes of drugs that has important implications for their clinical use and patient education to help reduce the burden of medication overuse headache.

Inhibition of NO production can counter both the cortical hyperexcitability and facilitation of trigeminal nociception that develop in the depleted 5-HT state. Therefore, NO is likely involved in the increase in both CSD events and CSD-evoked trigeminal nociception under decreased 5-HT conditions.

Serotonin (5-HT) is an important neurotransmitter involved in the control of neural and vascular responses. 5-HT depletion can induce several neurological disorders, including migraines. Studies on a cortical spreading depression (CSD) migraine animal model showed that the cortical neurons sensitivity, vascular responses, and nitric oxide (NO) production were significantly increased in 5-HT depletion. However, the involvement of NO in the cerebrovascular responses in 5-HT depletion remains unclear. This study aimed to investigate the role of NO in the CSD-induced alterations of cerebral microvessels in 5-HT depletion. Rats were divided into four groups: control, control with L-NAME treatment, 5-HT depleted, and 5-HT depleted with L-NAME treatment. 5-HT depletion was induced by intraperitoneal injection with para-chlorophenylalanine (PCPA) 3 days before the experiment. The CSD was triggered by KCl application. After the second wave of CSD, N-nitro-l-arginine methyl ester (L-NAME) or saline was intravenously injected into the rats with or without L-NAME treatment groups, respectively. The intercellular adhesion molecules-1 (ICAM-1), cell adhesion molecules-1 (VCAM-1), and the ultrastructural changes of the cerebral microvessels were examined. The results showed that 5-HT depletion significantly increased ICAM-1 and VCAM-1 expressions in the cerebral cortex. The number of endothelial pinocytic vesicles and microvilli was higher in the 5-HT depleted group when compared to the control. Interestingly, L-NAME treatment significantly reduced the abnormalities observed in the 5-HT depleted group. The results of this study demonstrated that an increase of NO production is one of the mechanisms involved in the CSD-induced alterations of the cerebrovascular responses in 5-HT depletion.

Background Migraine is a severe debilitating disorder of the brain that is ranked as the sixth most disabling disorder globally, with respect to disability adjusted life years, and there remains a significant unmet demand for an improved understanding of its underlying mechanisms. In conjunction with perturbed sensory processing, migraine sufferers often present with diverse neurological manifestations (premonitory symptoms) that highlight potential brainstem involvement. Thus, as the field moves away from the view of migraine as a consequence of purely vasodilation to a greater understanding of migraine as a complex brain disorder, it is critical to consider the underlying physiology and pharmacology of key neural networks likely involved. Discussion The current review will therefore focus on the available evidence for the brainstem as a key regulator of migraine biology and associated symptoms. We will further discuss the potential role of CGRP in the brainstem and its modulation for migraine therapy, given the emergence of targeted CGRP small molecule and monoclonal antibody therapies. Conclusion The brainstem forms a functional unit with several hypothalamic nuclei that are capable of modulating diverse functions including migraine-relevant trigeminal pain processing, appetite and arousal regulatory networks. As such, the brainstem has emerged as a key regulator of migraine and is appropriately considered as a potential therapeutic target. While currently available CGRP targeted therapies have limited blood brain barrier penetrability, the expression of CGRP and its receptors in several key brainstem nuclei and the demonstration of brainstem effects of CGRP modulation highlight the significant potential for the development of CNS penetrant molecules.

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