Stress-Induced Alteration in Chloride Transporters in the Trigeminal Nerve May Explain the Comorbidity between Depression and Migraine

Abstract

Migraine is frequently comorbid with depression and anxiety disorders. In the case of depression and panic disorder, the associations seem to be bidirectional. Stress (activation of the hypothalamic-pituitary-adrenal axis) is thought to be involved in increasing the attack frequency. In the current review, it is argued that elevated levels of cortisol increase the function of chloride-ion transporter NKCC1 and decrease the function of chloride-extruder KCC2 in the trigeminal nerve. This leads to a diminished inhibitory effect of gamma-aminobutyric acid (GABA) and an enhanced likelihood of a migraine attack. Since migraine attacks themselves are stressful, and since brain areas are activated that could contribute to panic, anxiety and depression, a number of self-sustaining circular processes could occur that would explain the bi-directionality of the associations. On the basis of this hypothesis, several novel therapeutic approaches to counter the pathological process can be proposed. These include inhibition of corticotrophin releasing factor by CRF1 receptor antagonists, blockade of adrenocorticotropic hormone (ACTH) at the MC2 receptor, and inhibition of the hyperactive NKCC1 chloride-transporter.