Hypoxia-related mechanisms inducing acute mountain sickness and migraine

Abstract

Experimental models of human diseases are vital for pathophysiological and therapeutic research. To investigate the initiation, maintenance, pathophysiology and even termination of a migraine/headache attack these models are urgently needed. Results from different studies promote the profound involvement of hypoxia in migraine and other primary/secondary headaches. The possible mechanisms that drive the induction of headaches through hypoxia are still unknown, but several modes of action, such as increased blood flow, dilation of cerebral arteries, the release of nitroglycerin, calcitonin gene-related peptide and adenosine or increased oxygen extraction are discussed intensively. In studies exposing healthy volunteers and people with a history of migraine to controlled normobaric hypoxia, our research group could demonstrate normobaric hypoxia to be an effective trigger of migraine headaches. Furthermore, a longitudinal measurement of calcitonin gene-related peptide (CGRP), during a hypoxic challenge in migraine patients, revealed increasing CGRP levels with prolonged hypoxic challenge. Since GRP has been linked to migraine and other headache disorders, hypoxia could be regarded as initiator for headaches on a neurotransmitter basis. Furthermore, it has been known for more than 2 decades from studies in vitro and in vivo that hypoxia can induce cortical spreading depression, a phenomenon believed to represent aura. Considering the increased prevalence of migraine in altitude populations and the solid pathophysiological changes on cellular and neurotransmitter level-the role of hypoxia should be investigated in greater detail by the headache community.

Keywords: AMS; CGRP; HAH; human migraine model; hypoxia; migraine.

FIGURE 1

Potential mechanism of hypoxia-induced cortical spreading depression (CSD) in migraine. Normobaric hypoxia can cause activation of redox-sensitive transient receptor potential channels (TRP) with further insertion of transmembrane proteins involved in signal propagation. Trigeminal afferents become sensitized via meningeal nociceptors inducing higher activity in central projections promoting cortical excitation leading to CSD. The initial wave of depolarization followed by tissue hypoxemia results in further activation and sensitization of pain processing pathways and thus migraine pain. Adapted from (Frank et al., 2020).