Aryl hydrocarbon receptors are involved in the pathogenesis of migraine

Abstract text (incl. figure legends and references)

Objective: Migraine is a prevalent disorder, with episodic attacks. Some patients experience an increase in attack frequency and develop chronic migraine. However, the underlying mechanisms of this progression are uncertain. The noradrenergic locus coeruleus (LC) has been involved in migraine chronicity. Recent studies found that selective activation of LC alleviates pain by reducing neuroinflammation. As the aryl hydrocarbon receptors (AhRs) are key regulators of the brain inflammatory responses, we, therefore, investigate the contribution of LC-expressed AhRs in migraine progression.

Methods: Using immunohistochemical approaches, we assessed the intracellular distribution and the expression levels of AhRs in the LC in a mice model of migraine induced by systemic administration of isosorbide dinitrate (ISDN; a nitric oxide donor). We also explored the effect of systemic AhR activation (by the indole agonist ITE) or inhibition (by the pure antagonist TMF) on cutaneous mechanical hypersensitivity (CMH) induced by ISDN.

Results: In naïve mice, AhRs were detected in 47.1 ± 3.4 % of LC noradrenergic neurons. Repeated ISDN administration resulted in a significant increase in this percentage (56.7 ± 3.4%, P<0.05). Interestingly, morphological alterations of LC neurons together with an increase of the soma and nucleus sizes were also observed. Behavioral testing showed that single or repeated TMF or ITE administrations did not affect cephalic mechanical sensitivity in naïve mice. In addition, ITE did not worsen the ISDN-induced CMH. However, a single administration of TMF effectively blocked ISDN-induced acute CMH, while daily administration was unable to prevent long-lasting CMH.

Conclusions: These data highlight, for the first time, the involvement of AhRs in the initiation but not in the maintenance of migraine.