Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice

Genetic loss of the voltage-gated sodium channel Na_v1.7 (Na_v1.7^-/-) 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_v1.7 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_v1.7 knockout (Na_v1.7^-/-) mice, but not those of Na_v1.8 knockout (Na_v1.8^-/-) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT₄ 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_v1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Na_v1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.