In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 10, No. 461 ( 2017-01-10)
Abstract:
Genetic loss of the voltage-gated sodium channel Na v 1.7 (Na v 1.7 −/− ) 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 Na v 1.7 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 Na v 1.7 knockout (Na v 1.7 −/− ) mice, but not those of Na v 1.8 knockout (Na v 1.8 −/− ) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT 4 receptors, which are Gα s -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 Gα i -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, Na v 1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Na v 1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.aah4874
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2017
