[HTML][HTML] Global Nav1. 7 knockout mice recapitulate the phenotype of human congenital indifference to pain

J Gingras, S Smith, DJ Matson, D Johnson, K Nye… - PloS one, 2014 - journals.plos.org
J Gingras, S Smith, DJ Matson, D Johnson, K Nye, L Couture, E Feric, R Yin, BD Moyer…
PloS one, 2014journals.plos.org
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 …
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.
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