Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

Michael S. Minett, Vanessa Pereira, Shafaq Sikandar, Ayako Matsuyama, Stéphane Lolignier, Alexandros H. Kanellopoulos, Flavia Mancini, Gian D. Iannetti, Yury D. Bogdanov, Sonia Santana-Varela, Queensta Millet, Giorgios Baskozos, Raymond MacAllister, James J. Cox, Jing Zhao and John N. Wood ()
Additional contact information
Michael S. Minett: Molecular Nociception Group, WIBR, University College London
Vanessa Pereira: Molecular Nociception Group, WIBR, University College London
Shafaq Sikandar: Molecular Nociception Group, WIBR, University College London
Ayako Matsuyama: Molecular Nociception Group, WIBR, University College London
Stéphane Lolignier: Molecular Nociception Group, WIBR, University College London
Alexandros H. Kanellopoulos: Molecular Nociception Group, WIBR, University College London
Flavia Mancini: Physiology and Pharmacology, University College London
Gian D. Iannetti: Physiology and Pharmacology, University College London
Yury D. Bogdanov: Molecular Nociception Group, WIBR, University College London
Sonia Santana-Varela: Molecular Nociception Group, WIBR, University College London
Queensta Millet: Molecular Nociception Group, WIBR, University College London
Giorgios Baskozos: Institute of Structural and Molecular Biology, UCL
Raymond MacAllister: UCL
James J. Cox: Molecular Nociception Group, WIBR, University College London
Jing Zhao: Molecular Nociception Group, WIBR, University College London
John N. Wood: Molecular Nociception Group, WIBR, University College London

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9967

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