Andrea M Harriott1,2,3, David Y Chung1,4, Aylin Uner5, Refik O Bozdayi6, Andreia Morais1, Tsubasa Takizawa1,7, Tao Qin1, Cenk Ayata1,2. 1. Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA. 2. Vascular Division, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. 3. Headache and Neuropathic Pain Division, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. 4. Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. 5. Baskent University Medical School, Ankara, Turkey. 6. Ankara University, School of Medicine, Ankara, Turkey. 7. Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
Abstract
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 used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. METHODS: Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, 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, whereas a single SD did not. Repeated SDs 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 end point. INTERPRETATION: Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.
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 used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. METHODS: Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, 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, whereas a single SD did not. Repeated SDs 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 end point. INTERPRETATION: Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.
Authors: Dale J Langford; Andrea L Bailey; Mona Lisa Chanda; Sarah E Clarke; Tanya E Drummond; Stephanie Echols; Sarah Glick; Joelle Ingrao; Tammy Klassen-Ross; Michael L Lacroix-Fralish; Lynn Matsumiya; Robert E Sorge; Susana G Sotocinal; John M Tabaka; David Wong; Arn M J M van den Maagdenberg; Michel D Ferrari; Kenneth D Craig; Jeffrey S Mogil Journal: Nat Methods Date: 2010-05-09 Impact factor: 28.547
Authors: Katharina Eikermann-Haerter; Izumi Yuzawa; Tao Qin; Yumei Wang; Kwangyeol Baek; Young Ro Kim; Ulrike Hoffmann; Ergin Dilekoz; Christian Waeber; Michel D Ferrari; Arn M J M van den Maagdenberg; Michael A Moskowitz; Cenk Ayata Journal: J Neurosci Date: 2011-04-13 Impact factor: 6.167
Authors: C Lovati; D D'Amico; S Rosa; M Suardelli; E Mailland; P Bertora; S Pomati; C Mariani; G Bussone Journal: Neurol Sci Date: 2007-05 Impact factor: 3.307
Authors: Zachariah Bertels; Isaac J Dripps; Pal Shah; Laura S Moye; Alycia F Tipton; Kendra Siegersma; Amynah A Pradhan Journal: Neurobiol Pain Date: 2022-07-11
Authors: Lite Yang; Mengyi Xu; Shamsuddin A Bhuiyan; Jia Li; Jun Zhao; Randall J Cohrs; Justin T Susterich; Sylvia Signorelli; Ursula Green; James R Stone; Dan Levy; Jochen K Lennerz; William Renthal Journal: Neuron Date: 2022-03-28 Impact factor: 18.688