title: Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.
abstract: Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Minett
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pereira
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Shafaq
authors.initials: S
authors.lastname: Sikandar
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Ayako
authors.initials: A
authors.lastname: Matsuyama
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lolignier
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Alexandros H
authors.initials: AH
authors.lastname: Kanellopoulos
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Mancini
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Gian D
authors.initials: GD
authors.lastname: Iannetti
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Yury D
authors.initials: YD
authors.lastname: Bogdanov
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Santana-Varela
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Queensta
authors.initials: Q
authors.lastname: Millet
authors.affiliation: Institute of Structural and Molecular Biology, UCL, London WC1E 6BT, UK.
authors.forename: Giorgios
authors.initials: G
authors.lastname: Baskozos
authors.affiliation: Department of Medicine, UCL, London WC1E 6BT, UK.
authors.forename: Raymond
authors.initials: R
authors.lastname: MacAllister
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Molecular Nociception Group, WIBR, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
mesh_terms: D000328:Adult; D000818:Animals; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D000699:Pain Insensitivity, Congenital / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D012677:Sensation; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D004745:Enkephalins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C503479:Scn9a protein, mouse