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

Identification of Nav1.7 as responsible for the absence of pain sensitivity in humans has prompted the investigation of drugs targeting this channel as pain relievers. However, this has so far not been effective. Isensee et al . found that the absence of this channel altered the signaling efficiency of G protein–coupled receptors (GPCRs) in the peripheral pain-sensing neurons of the dorsal root ganglia. The balance of pronociceptive (pain-promoting) serotonin signaling mediated by the 5-HT4 receptor and antinociceptive (pain-relieving) opioid signaling mediated by the mu opioid receptor (MOR) was altered. Mice lacking Nav1.7 had much more efficient signaling by the opioid arm, shifting the balance such that the neurons were much less responsive to pronociceptive signals and much more responsive to antinociceptive signals.