Isensee, J;
Krahe, L;
Moeller, K;
Pereira, V;
Sexton, JE;
Sun, X;
Emery, E;
... Hucho, T; + view all
(2017)
Synergistic regulation of serotonin and opioid signaling contribute to pain insensitivity in Na(v)1.7 knockout mice.
Science Signaling
, 10
(461)
10.1126/scisignal.aah4874.
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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-HT4 receptors, 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.
| Type: | Article |
|---|---|
| Title: | Synergistic regulation of serotonin and opioid signaling contribute to pain insensitivity in Na(v)1.7 knockout mice |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/scisignal.aah4874 |
| Publisher version: | http://dx.doi.org/10.1126/scisignal.aah4874 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, SODIUM-CHANNEL NA(V)1.7, ADENYLATE-CYCLASE, PROTEIN-KINASE, DIABETIC-NEUROPATHY, SENSORY NEURONS, 5-HT4 RECEPTOR, UNITED-STATES, PHOSPHORYLATION, TOLERANCE, 5-HYDROXYTRYPTAMINE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1536001 |
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