No pain no . . . smell?
Though less catchy than the time-honored platitude, new evidence has emerged showing that, indeed, a certain genetic mutation which normally results in the inability to feel pain also adversely affects the sense of smell.
It may be difficult to think about how the sensations of pain and smell could be linked, especially because they seem so very different, but the truth is that the similarity between them is quite basic and fundamental: both pain and olfaction require the activity of a single ion channel called Na(v)1.7.
Na(v)1.7 is a voltage-gated sodium channel and, according to the work of researchers at the University of Saarland School of Medicine, it plays a crucial role in the signaling cascades in both pain sensation and olfaction. The research team was led by Frank Zufall.
Their work has focused on studies of humans with a congenital inability to feel pain. Interestingly, the patients examined for the present study, though probably treated throughout their lives for their painlessness and the troubles caused therein, never even noticed that they were anosmic — that they can’t smell. In the process of trying to better characterize and study congenital painlessness, however, researchers discovered that Na(v)1.7 is expressed in more sensory systems than was previously thought.
In further work with mice bred to lack the analog of the gene encoding Na(v)1.7, called SCN9A, the researchers also found that mice who lacked the channel also lacked the sense of smell. However, the problem wasn’t that olfactory receptors couldn’t sense the odorants in the air. Weiss and Zufall’s work shows that the sensory neurons themselves still respond to the odor stimuli; however, the reason for mice’s inability to smell lies in the fact that signaling from the olfactory receptor neurons to their target cells is abolished in Na(v)1.7 mutants.
This evidence supports the idea that Na(v)1.7 is an important component not for actually detecting sensory stimuli, but instead, the sodium channel helps transduce the electro-chemical signals sent from one neuron to another when a stimulus starts a chain of sensory activation.
Most likely, Na(v)1.7 is helping to keep action potentials robust and moving quickly along the length of olfactory sensory neurons’ axons. Without working Na(v)1.7 channels, these cells are simply unable to pass on the message that an odorant has been detected.
It is possible that similar mechanisms are at work in pain sensation, wherein a painful stimulus can activate a receptive cell, but if that cell has no ability to pass the signal on to the next step in the pathway to sensation, then it would be impossible to perceive pain at all. This could of course be a potential gold mine for the pharmaceutical industry, which is constantly seeking novel pain killers.
By targeting Na(v)1.7, it is possible that drugs could temporarily shut down the pain pathway, leaving people pain-free in the meantime. The only downside is, of course, that while the drug inhibits pain sensation it would also interfere with people’s sense of smell — which might or might not be worth the benefit of such drugs.
Discussions of the potential side effects of any Na(v)1.7–targeting painkillers bring up an interesting difference between the current findings in humans and in mice: mice lacking Na(v)1.7 and therefore also lacking the sense of smell show dramatic and important deficiencies in most smell-based or smell–guided behaviors. However, anosmic humans can literally go entire lifetimes without ever noticing their deficiency. So perhaps temporary pain relief at the expense of a sense of smell might not be so bad for most humans. Although the sense of smell might not be as important for humans as it is for mice, the fact remains that the current findings provide an important clue as to what biochemical components are being utilized in the olfactory sensory cascade.
Further experiments will now have to go further and develop more in-depth models of the molecular mechanisms underlying smell.
