title: Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.
abstract: Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1.7 knockout (Nav1.7-/-) mice, but not those of Nav1.8 knockout (Nav1.8-/-) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT4receptors, which are Gαs-coupled GPCRs that stimulate the production of cyclic adenosine monophosphate resulting in protein kinase A (PKA) activity, as well as reduced abundance of the RIIβ regulatory subunit of PKA. Simultaneously, the efficacy of antinociceptive opioid signaling mediated by the Gαi-coupled mu opioid receptors was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Nav1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Nav1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, 50931 Cologne, Germany. joerg.isensee@uk-koeln.de tim.hucho@uk-koeln.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Isensee
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, 50931 Cologne, Germany.
authors.forename: Leonhardt
authors.initials: L
authors.lastname: Krahé
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, 50931 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Moeller
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pereira
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Sexton
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Sun
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Emery
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, Robert Koch Str. 10, 50931 Cologne, Germany. joerg.isensee@uk-koeln.de tim.hucho@uk-koeln.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Hucho
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D007211:Indoles; D062556:NAV1.7 Voltage-Gated Sodium Channel; D017450:Receptors, Opioid, mu; C503479:Scn9a protein, mouse; D012702:Serotonin Antagonists; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D013779:Tetrodotoxin; C082871:GR 113808