Fig. 7. Synergistic regulation of pro- and anti-nociceptive signaling in Na_v1.7-deficient mice.

Nav1.7-deficiency results in a reduction in 5-HT₄ receptors, due to decreased gene expression, and the RIIβ subunit (and presumably also the catalytic subunit) of PKA. Thereby, the pro-nociceptive input in sensory neurons (red) is strongly reduced. Simultaneously, the anti-nociceptive input (green) is increased due to enhanced opioid receptor activity and increased expression of the gene encoding the precursor of endogenous opioid peptides (enkephalins). This synergistic regulation shifts the balance toward anti-nociceptive signaling and thus contributes to the pain-free phenotype in Na_v1.7-deficient mice.