title: Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice.
abstract: Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel α1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents.
authors.affiliation: Department of Psychology and Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Mona Lisa
authors.initials: ML
authors.lastname: Chanda
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Tuttle
authors.forename: Inna
authors.initials: I
authors.lastname: Baran
authors.forename: Cori
authors.initials: C
authors.lastname: Atlin
authors.forename: Daniella
authors.initials: D
authors.lastname: Guindi
authors.forename: Georgia
authors.initials: G
authors.lastname: Hathaway
authors.forename: Nyrie
authors.initials: N
authors.lastname: Israelian
authors.forename: Jeremy
authors.initials: J
authors.lastname: Levenstadt
authors.forename: Daniel
authors.initials: D
authors.lastname: Low
authors.forename: Lynn
authors.initials: L
authors.lastname: Macrae
authors.forename: Louise
authors.initials: L
authors.lastname: O'Shea
authors.forename: Alex
authors.initials: A
authors.lastname: Silver
authors.forename: Elaina
authors.initials: E
authors.lastname: Zendegui
authors.forename: A
authors.initials: A
authors.lastname: Mariette Lenselink
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics*; D020864:Calcium Channels, N-Type; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005243:Feces; D005260:Female; D007839:Functional Laterality / Q000235:genetics*; D006261:Headache / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics*; D010147:Pain Measurement; D020795:Photophobia / Q000209:etiology*; D013315:Stress, Psychological / Q000209:etiology*; D014230:Triazoles / Q000627:therapeutic use; D014363:Tryptamines / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D009020:Morphine; D014230:Triazoles; D014363:Tryptamines; C492923:Cacnb1 protein, mouse; C093622:rizatriptan