Optogenetic spreading depression elicits trigeminal pain and anxiety behavior.

Objective Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we employed a novel minimally invasive optogenetic SD induction method and examined the effect SD on behavior. Methods Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. Endpoints including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory were examined in male and female mice. Results A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, while single SD did not. Repeated SD also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any endpoint. Interpretation Altogether, these data show a clinically congruent causal relationship between SD, trigeminal pain and anxiety behavior possibly reflecting SD modulation of hypothalamic, thalamic and limbic mechanisms. This article is protected by copyright. All rights reserved.