The mechanism of analgesia in NaV1.7 null mutants

Summary Deletion of SCN9A encoding the voltage-gated sodium channel Na V 1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na V 1.7 in sensory neurons of mice also abolishes pain suggesting the locus of analgesia is the nociceptor. Here we demonstrate that Na V 1.7 knockout mice have essentially normal nociceptor activity using in vivo calcium imaging and extracellular recording. However, glutamate and substance P release from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also substantially reversed by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid-independent. Male and female humans with Na V 1.7 null mutations show naloxone reversible analgesia. Thus opioid-dependent inhibition of neurotransmitter release is the principal mechanism of Na V 1.7 null analgesia in mice and humans.