Two distinct mechanisms for Nav1.7 null analgesia

Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Na v 1.7 and Na v 1.8. Genetic deletion of Na v 1.8 in mice leads to a loss of pain, and antagonists are effective analgesics. Complete embryonic loss of Na v 1.7 in humans or in mouse sensory neurons leads to profound analgesia substantially mediated by endogenous opioid signaling, and anosmia that is opioid independent. Autonomic function appears to be normal. Adult deletion of Na v 1.7 in sensory neurons also leads to analgesia with diminished sensory neuron excitability but there is no opioid component of analgesia. Pharmacological inhibition of Na v 1.7 leads to dramatic side-effects on the autonomic nervous system. Here we compare and contrast the distinct embryonic and adult null mechanisms of Nav1.7 loss-of-function analgesia. We describe an endogenous opioid mechanism of analgesia that provides new opportunities for therapeutic intervention and pain relief. Summary In contrast to Na v 1.8, Na v 1.7, a genetically validated human pain target is unsuitable for small molecule drug development because of its wide spread expression both centrally and peripherally.