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

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

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.

Adult, Animals, Enkephalins, Female, Humans, Male, Mice, Mice, Knockout, NAV1.7 Voltage-Gated Sodium Channel, Pain Insensitivity, Congenital, Sensation, Sensory Receptor Cells, Journal Article, Research Support, Non-U.S. Gov't
Minett, Michael S.
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Pereira, Vanessa
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Sikandar, Shafaq
dbcae87d-7c8b-49fe-b904-14a571837065
Matsuyama, Ayako
03e927b8-b50d-46ba-a237-202bcd6aed15
Lolignier, Stéphane
856d8a7f-4a7c-4eed-9608-9de057a64691
Kanellopoulos, Alexandros H.
90fbf183-9cd6-4ded-a1ae-5077587e3dea
Mancini, Flavia
fb3a5b9f-9c14-403a-bdea-6a7ceea79eb7
Iannetti, Gian D.
f552e83f-1be9-427c-af46-1aa456505616
Bogdanov, Yury D.
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Santana-Varela, Sonia
da067c0f-bfc4-4a5a-8f54-2e28b5c3bcde
Millet, Queensta
92c8c020-157c-4f74-b214-5e2fb34636dc
Baskozos, Giorgios
ac2d5db5-4ecb-4f75-a6eb-bb6c57f8b8d6
MacAllister, Raymond
9f4b26b2-72e1-4ccf-9338-362d6193085b
Cox, James J.
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Zhao, Jing
b79522c0-ea16-4dd1-8405-cec85df7b9f5
Wood, John N.
afbfb1c4-d021-4f51-88d2-9e481532b797
Minett, Michael S.
d767767a-4b0f-4090-a715-70a936fc37c6
Pereira, Vanessa
e70da157-1f13-43b9-a89b-e0141e11e9e3
Sikandar, Shafaq
dbcae87d-7c8b-49fe-b904-14a571837065
Matsuyama, Ayako
03e927b8-b50d-46ba-a237-202bcd6aed15
Lolignier, Stéphane
856d8a7f-4a7c-4eed-9608-9de057a64691
Kanellopoulos, Alexandros H.
90fbf183-9cd6-4ded-a1ae-5077587e3dea
Mancini, Flavia
fb3a5b9f-9c14-403a-bdea-6a7ceea79eb7
Iannetti, Gian D.
f552e83f-1be9-427c-af46-1aa456505616
Bogdanov, Yury D.
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Santana-Varela, Sonia
da067c0f-bfc4-4a5a-8f54-2e28b5c3bcde
Millet, Queensta
92c8c020-157c-4f74-b214-5e2fb34636dc
Baskozos, Giorgios
ac2d5db5-4ecb-4f75-a6eb-bb6c57f8b8d6
MacAllister, Raymond
9f4b26b2-72e1-4ccf-9338-362d6193085b
Cox, James J.
6ff72a70-d779-44fc-be22-945b80b4c4a4
Zhao, Jing
b79522c0-ea16-4dd1-8405-cec85df7b9f5
Wood, John N.
afbfb1c4-d021-4f51-88d2-9e481532b797

Minett, Michael S., Pereira, Vanessa, Sikandar, Shafaq, Matsuyama, Ayako, Lolignier, Stéphane, Kanellopoulos, Alexandros H., Mancini, Flavia, Iannetti, Gian D., Bogdanov, Yury D., Santana-Varela, Sonia, Millet, Queensta, Baskozos, Giorgios, MacAllister, Raymond, Cox, James J., Zhao, Jing and Wood, John N. (2015) Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature Communications, 6, [8967]. (doi:10.1038/ncomms9967).

Record type: Article

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.

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More information

Accepted/In Press date: 21 October 2015
e-pub ahead of print date: 4 December 2015
Keywords: Adult, Animals, Enkephalins, Female, Humans, Male, Mice, Mice, Knockout, NAV1.7 Voltage-Gated Sodium Channel, Pain Insensitivity, Congenital, Sensation, Sensory Receptor Cells, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 417374
URI: http://eprints.soton.ac.uk/id/eprint/417374
PURE UUID: a0f9a2d7-2b46-4707-bb59-749441c4507a
ORCID for Yury D. Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890

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Date deposited: 30 Jan 2018 17:30
Last modified: 17 Dec 2019 01:34

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Contributors

Author: Michael S. Minett
Author: Vanessa Pereira
Author: Shafaq Sikandar
Author: Ayako Matsuyama
Author: Stéphane Lolignier
Author: Alexandros H. Kanellopoulos
Author: Flavia Mancini
Author: Gian D. Iannetti
Author: Sonia Santana-Varela
Author: Queensta Millet
Author: Giorgios Baskozos
Author: Raymond MacAllister
Author: James J. Cox
Author: Jing Zhao
Author: John N. Wood

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