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

• Published in: Nature communications Vol. 6; no. 1; p. 8967
• Main Authors: 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, Wood, John N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2015; Nature Publishing Group
• Subjects: 631/378/1689/2610; 631/45/269/1152; 631/80/86/2372; 692/700/565/2194; 96; 96/106; 96/95; Adult; Animals; Enkephalins - genetics; Enkephalins - metabolism; Female; Humanities and Social Sciences; Humans; Life Sciences; Male; Mice; Mice, Knockout; multidisciplinary; NAV1.7 Voltage-Gated Sodium Channel - genetics; NAV1.7 Voltage-Gated Sodium Channel - metabolism; Neurons and Cognition; Pain Insensitivity, Congenital - genetics; Pain Insensitivity, Congenital - metabolism; Pain Insensitivity, Congenital - physiopathology; Pharmaceutical sciences; Pharmacology; Science; Science (multidisciplinary); Sensation; Sensory Receptor Cells - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9967

Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Na v 1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Na v 1.7 are weak analgesics. We investigated whether Na v 1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Na v 1.7 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, Na v 1.8-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 Na v 1.7-null mutant mice, as well as in a human Na v 1.7-null mutant. These data suggest that Na v 1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids. Na v 1.7 channels are known to regulate pain perception in humans and mice. Here, the authors provide evidence that Na v 1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Na v 1.7 nulls.