Researchers from University College London (UCL) have discovered a key element for the absolute painlessness experienced by some people. The mutation in the sodium channel Nav1.7 not only blocks pain pathways, but also increases expression levels of natural opioid peptides. The findings were published in Nature Communications.
The SCN9A gene encodes the protein Nav1.7, which constitutes a voltage-gated sodium channel through which electrical signals between neural cells carry pain information. People born with a mutated, non-functional Nav1.7 don’t experience pain. Researchers hypothesized that blocking the Nav1.7 channel would be a good strategy for pain treatment in patients, but the multiple drugs developed to that effect have a low performance. The UCL researchers decided to experiment with transgenic mice lacking Nav1.7 to see if it had additional functions. The mutant mice experienced no pain, just like humans with the mutated version of the sodium channel. However, gene expression experiments revealed that mice lacking Nav1.7 had higher levels of the enkephalin precursor Penk mRNA. Enkephalin is an opioid peptide involved in the perception of pain. When the researchers checked enkephalin levels in sensory neurons, they also found it was present in higher levels in Nav1.7-null mutant mice. Later, they checked enkephalin expression in humans, and confirmed that levels were also higher when Nav1.7 is mutated.
Therapy: low dose opioids + Nav1.7 blockers
John N. Wood and his team discovered that the painlessness is a consequence of Nav1.7 blocking and high expression of opioid peptides combined. When Nav1.7-lacking mice and humans were treated with naloxone, an opioid blocker, both groups were able to feel pain. The researchers plan to file a patent for a pain treatment based on a combination of Nav1.7 blockers and low doses of opioids. When Nav1.7 is mutated, there is no need to deliver huge amounts of opioids: this solves the dependence and tolerance problems experienced in morphine-based treatments.
Human trials for this treatment will start in 2017. Different drug combinations will be tested to find a solution for the millions of people suffering from chronic pain.