Sodium channels Na1.7, Na1.8 and pain; two distinct mechanisms for Na1.7 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 Na1.7 and Na1.8. Genetic deletion of Na1.8 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 Na1.7 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 Na1.7 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 Na1.7 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 Na1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na1.7 channel. Here we show that sensory neuron sodium channels Na1.1, Na1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.