Hi found this, thought the end of it was kind of wild (“More complexity comes from…”) :
That Nav1.7 knockouts have an upregulation in opioids; maybe some of the pain relief is opioid-mediated.
One person with CIP (insensitivity to pain) can actually feel pain again after being given naloxone (anti-opioid).
Meds blocking only Nav1.7 might not be as effective by themselves as compared to when they are combined with things that target at least another sodium channel, or when they are combined with subtherapeutic opioid doses.
Some other articles talking about this -
“Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid.”
and fig 1 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950419/ :
" Complete channel block in wild type DRG neurons in culture with high levels (0.5 µM) of tetrodotoxin (TTX), a sodium channel pore blocker , also leads to upregulated expression of opioid peptides in sensory neurons. However, TTX at five times the IC50 for Nav1.7 does not lead to enhanced enkephalin expression, suggesting that any compound that recapitulates the CIP phenotype of loss-of-function mutants will have to provide 100% Nav1.7 channel block, which is an unrealistic pharmacological goal. As opioid-dependent analgesia seems to account for the vast majority of the CIP phenotype, intriguingly implying a life-long endogenous opioid action with no tolerance , a combination of a specific Nav1.7 antagonist and low doses of opioids or enkephalinase blockers should recapitulate CIP if this mechanism is correct. In animal models, this conclusion has been confirmed for a number of acute, inflammatory and neuropathic pain models.[1,43,44] In Figure 1, the combination of a selective toxin that blocks Nav1.7, phlotoxin 1, with buprenorphine at concentrations that are ineffective alone produces a dramatic analgesia when applied together. How does the presence of a voltage-gated sodium channel influence the expression of opioid peptides? This is a fascinating mechanistic puzzle…"