Open AccessNociceptor-specific gene deletion reveals a major role for Na v 1.7 (PN1) in acute and inflammatory pain
Author(s) -
Mohammed A. Nassar,
L Caroline Stirling,
Greta Forlani,
Mark D. Baker,
Elizabeth Matthews,
Anthony H. Dickenson,
John N. Wood
Publication year - 2004
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0404915101
Subject(s) - nociceptor , nociception , noxious stimulus , hyperalgesia , gene knockout , sodium channel , knockout mouse , cre recombinase , chemistry , conditional gene knockout , trpv1 , neuroscience , microbiology and biotechnology , medicine , endocrinology , biology , gene , transgene , genetically modified mouse , genetics , transient receptor potential channel , sodium , receptor , phenotype , organic chemistry
Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Nav 1.7, Nav 1.8, and Nav 1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Nav 1.7 (PN1) in pain pathways. A global Nav 1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Nav 1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Nav 1.8 locus to generate heterozygous mice expressing Cre recombinase in Nav 1.8-positive sensory neurons. Crossing these animals with mice where Nav 1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Nav 1.7 gene,SCN9A . Dominant Nav 1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Nav 1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.