title: Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.
abstract: Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Gingras
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Matson
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Kim
authors.initials: K
authors.lastname: Nye
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Couture
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Elma
authors.initials: E
authors.lastname: Feric
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Ruoyuan
authors.initials: R
authors.lastname: Yin
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Moyer
authors.affiliation: Department of Pharmaceutics Research & Development, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.affiliation: Department of Pathology, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.affiliation: Department of Comparative Animal Research, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Rudolph J
authors.initials: RJ
authors.lastname: Beiler
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Annika B
authors.initials: AB
authors.lastname: Malmberg
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Stefan I
authors.initials: SI
authors.lastname: McDonough
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009420:Nervous System / Q000473:pathology / Q000503:physiopathology; D000857:Olfaction Disorders / Q000235:genetics / Q000503:physiopathology; D000699:Pain Insensitivity, Congenital / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D010641:Phenotype; D011984:Sensory Receptor Cells / Q000502:physiology
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C503479:Scn9a protein, mouse