In Northern Pakistan, a ten-year old street performer awed and horrified crowds with his ability to place knives through his arms and walk across burning coals all seemingly without pain. Closer examination by physicians revealed that he could perceive sensations of touch, differentiate between hot and cold temperatures, distinguish between a tickle and applied pressure, but had no aversion to painful stimuli. This seemingly superhero power has dangerous and deadly consequences for those afflicted with this mysterious condition. Just imagine what would happen if touching a scorching hot stove elicited no response by your brain. Yes, you would undoubtedly impress your friends, but the burn to your hand would require an immediate hospital visit. Pain is in fact a crucial survival mechanism that instructs us in the ways of injury avoidance and aversion from harmful situations. If a broken bone did not hurt, it is unlikely that an individual would avoid using the limb until it healed.
Scientists have zeroed in on the cause of this dangerous indifference to pain. Gain-of-function mutations in the SCN9A gene lead to severe neuropathic pain whereas a loss-of function mutation results in the inability to experience pain (Cox et al., 2006). SCN9A encodes a voltage-gated sodium channel (specifically, Nav1.7 for all of you channel connoisseurs) that regulates sensory neuron excitability. Sodium channels enable positively charged sodium ions to be transported in order to play a role in generating electrical signals crucial for communication between neurons. This sodium channel is preferentially expressed in peripheral neurons of the dorsal root ganglia and in the majority of nociceptors (pain- or damage-sensing neurons) as outlined in this infographic. In patients who are unable to feel pain, SCN9A produces a protein that cannot function. (Article continues below)
Neuropathic pain results from diseases of the somatosensory system and involves chronic pain that is usually accompanied by tissue injury. In neuropathic pain, the nerve fibers become damaged leading to incorrect signals being sent to pain centers in the brain. One intense example of neuropathic pain is phantom limb syndrome. In the aftermath of an injury leading to the loss of a limb, the brain still gets pain messages from the nerves that originally carried signals from the missing limb. When the nerves misfire, the result is pain.
In our daily lives we see frequent examples of individuals having different thresholds for pain tolerance – one child is kicked during a soccer match and runs off the field screaming while another carries on through an injury to score a goal. It is possible that mutations that cause sodium channels to open too easily and close too sluggishly could underlie sensitivity to pain. Since the mutation in people who are pain-free results from inactive sodium channels, it would make logical sense that a pharmacological block in sodium channels should provide pain relief. The problem with this theory is that if you block all sodium channels, you die. In fact, the reason puffer fish is so toxic is that tetrodotoxin blocks all voltage-gated sodium channels. Thus, a drug that selectively blocked a specific type of sodium channel would have to be used to safely alleviate pain. But before we get too excited about using drugs to mimic the SCN9A mutation that prevents the experience of pain, let’s remember the benefits of those painful lessons that taught us to avoid jumping out of trees and entering boxing matches with bigger siblings.
Cox J.J., Reimann F., Nicholas A.K., Thornton G., Roberts E., Springell K., Karbani G., Jafri H., Mannan J., Raashid Y. & Al-Gazali L. (2006). An SCN9A channelopathy causes congenital inability to experience pain, Nature, 444 (7121) 894-898. DOI: 10.1038/nature05413
Images made by Jooyeun Lee, Jillian L. Shaw, Kate Jones, and Ryan Jones
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