Sodium channels Na_v1.7, Na_v1.8 and pain; two distinct mechanisms for Na_v1.7 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_v1.7 and Na_v1.8. Genetic deletion of Na_v1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Na_v1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal. Adult deletion of Na_v1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Na_v1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Na_v1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na_v1.7 channel. Here we show that sensory neuron sodium channels Na_v1.1, Na_v1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na_v1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na_v1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.