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

Hans O Kalkman

doi:10.3390/psychiatryint1020006

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.

Highlights

Migraine is characterized by recurring, disabling headache attacks that last somewhere between four and 72 h
These fibers originate from the trigeminal ganglion and project to an area in the medulla and brainstem designated as the trigeminocervical complex, including the trigeminal nucleus caudalis [3]
Optical imaging of evoked synaptic responses using a voltage- sensitive dye, revealed that post-synaptic gamma-aminobutyric acid (GABA) actions at the injured side were excitatory. This down-regulation of KCC2 in the trigeminocervical complex may result in an excitatory switch by impairing postsynaptic GABA inhibition [34]. This is a model of neuropathic pain and not of migraine, it is conceivable that in patients with chronic migraine the trigeminal nerve might become hyperexcitable owing to a GABA-disinhibitory effect of cortisol

Summary

Introduction

Migraine is characterized by recurring, disabling headache attacks that last somewhere between four and 72 h. Nociceptive information from cranial blood vessels in the pia-, dura-, and arachnoid mater is transmitted via Aδand C-type sensory fibers [2,3]. These fibers originate from the trigeminal ganglion and project to an area in the medulla and brainstem designated as the trigeminocervical complex, including the trigeminal nucleus caudalis [3]. It is hypothesized that an altered processing of sensory input into the trigeminal nucleus caudalis accounts for many of the temporal and symptomatic features of migraine [3,8]. Certain branches of the trigeminal nerve innervate extracranial tissues and since information-processing by sensory nerves is bidirectional, central activation of the trigeminus is noticeable in the skin of the head and neck [3]

Migraine Is Co-Morbid with Panic Disorder and Depression

GABA Receptors and Functional Responses of the Trigeminal Nerve

Stress Modifies the Activity of Chloride Transporters

Discussion

Conclusions