In today’s issue of Nature, Cox et al report on a genetic study of an extended family from northern Pakistan, six members of which are completely insensitive to pain:
The index case for the present study was a ten-year-old child, well known to the medical service after regularly performing street theatre. He placed knives through his arms and walked on burning coals, but experienced no pain. He died before being seen on his fourteenth birthday, after jumping off a house roof. Subsequently, we studied three further consanguineous families in which there were individuals with similar histories of a lack of pain appreciation…All six affected individuals had never felt any pain, at any time, in any part of their body. Even as babies they had shown no evidence of pain appreciation. None knew what pain felt like, although the older individuals realized what actions should elicit pain…All had injuries to their lips…and/or tongue…caused by biting themselves in the first 4 yr of life. All had frequent bruises and cuts, and most had suffered fractures or osteomyelitis, which were only diagnosed in retrospect because of painless limping or lack of use of a limb.
Being insensitive to pain is, of course, very dangerous, as it makes one oblivious to potentially fatal injuries. The condition presented by the people in the study occurs as a result of an extremely rare genetic mutation in the SCN9A gene, which is found on chromosome 2. The mutation is in the SCN9A gene, which encodes a subunit of a sodium-gated ion channel called Nav1.7, and results in a truncated ion channel protein which does not function. The condition is inherited in an autosomal-recessive manner, and has been named ‘channelopathy-associated insensitivity to pain’ by the authors.
Nav1.7 sodium channels are expressed in small diameter primary sensory neurons (nociceptors) and in neurons of the sympathetic ganglia. The protein was implicated in nociception by studies which showed that it is overexpressed in animal models of inflammatory pain, and hyperactive in erythromelalgia, a condition in which severe burning pain is elicited by warm temperatures.
The loss-of-function mutation in the SCN9A gene leads to a complete insensitivity to pain, while leaving all the other sensory modalities intact – the people with the mutation are still sensitive to touch, temperature changes and proprioception (the position of their limbs in space). These modalities are not mediated by the sensory neurons which convey pain stimuli to the spinal cord, suggesting that Na1.7 has different functions in different classes of sensory neurons.
Nociceptors and sensory neurons in the sympatheic ganglion express dozens of different ion channels and receptors, all of which are involved in generating nervous impulses related to sensoryinformation. So why is it that a loss-of-function mutation in just one results in a complete insensitivity to pain? Nav1.7 amplifies the changes in membrane voltage brought about by other ion channels in response to painful stimuli. This sensitizes the cells to those stimuli, making them more likely to send electrical signals towards the brain.
The findings of this study point to Nav1.7 as a target for novel analgesics. The people in the study are otherwise healthy and have ‘normal’ levels of intelligence, so it is possible that any analgesics which target Nav1.7 may alleviate pain without having any side effects.
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