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Essay

The bliss of pain

Why it's all in your head

Samiha S. Shaikh 6 April 2014

www.lablit.com/article/817

Connections: pain signals need balance

Perhaps life without pain isn’t so rosy after all

Editor's note: We are pleased to publish the winning entry for this year's British Society for Cell Biology's Writing Prize, of which LabLit.com was the judge. Congratulations Samiha!

Stubbing your toe, scalding your hand, breaking your leg, eating a pound of chillies...Can you imagine life without pain? At first it seems like an excellent idea, making us blissfully oblivious to all of these unwanted discomforts and allowing us to get on with our lives without interruptions. After all, surely such an unpleasant sensation can have no advantage?

Think again. In fact, it may come as a surprise that we don’t have to imagine a completely pain free life at all; rather than being the stuff of science fiction, for people with congenital insensitivity to pain (CIP) this is reality. They have a complete inability to sense pain from birth, similar to a faulty circuit in which the switch does not work and the light bulb does not light up. Perhaps life without pain isn’t so rosy after all. During teething babies want to bite on anything in sight, including their tongues and lips. As they don’t feel pain, babies with CIP chew right through their tongues and lips. They later suffer other injuries that go unnoticed including severe corneal abrasions, as a result of scratching or rubbing the eyes too hard and fractures or burns. Without the warning signals that pain provides, a child with CIP can break their leg yet walk on it all day or cause sight-damaging corneal problems without noticing. As a result of all the complications, people with CIP typically have a much-reduced life expectancy.

So if putting up with some pain means you live longer, I think most peoples’ choice would be the same as mine! But what if we feel too much pain? At the other end of the spectrum are people with the condition primary erythromelalgia (PE) who have a much lower pain threshold and hence feel too much pain. Their light bulb lights up too brightly when the switch is turned on. These people suffer from burning pain in the feet, legs and hands which is easily triggered by exercise or standing for too long or even just by warm weather. Even wearing shoes can be so painful that it prevents people from going to work or school.

While both a lack of and excessive pain can be devastating, chronic pain can be useless and maladaptive. Normally pain signals are detected by receptors called nociceptors in damaged tissues and passed as electric impulses via pain nerves to the pain sensing centres in the brain. In the face of a prolonged barrage of signals, the system can become disrupted and dissociated from tissue damage so that the pain centres remain active constantly even after the damage has resolved. The light bulb continues to light up even when the switch is off. ‘So this pain is all in my head?’ comes the question. Of course it is, but then so is the pain you feel when you stub your toe and this does not make either any less real. Pain is ‘felt’ in the brain rather than in the periphery.

Our responses to pain are to a degree determined by our genes. Indeed, the underlying cause of CIP and PE is genetic. Surprisingly, although the diseases are completely contrasting, both CIP and PE are caused by mutations in the gene SCN9A.

You may well be wondering how mutations in the same gene, SCN9A, can cause pain insensitivity and also increased pain perception. By taking a look at the function of SCN9A we can gain an understanding as to why mutations in the same gene result in two diseases that are contrasting. SCN9A is a sodium channel that is located on nociceptors and without it, the transmission of a painful stimulus from sensory nerves to the brain cannot occur. In CIP, patients have a shorter form of SCN9A that cannot perform its usual function and ultimately doesn’t allow for the transmission of painful stimuli from the skin to the brain. In contrast mutations that cause PE increase the activity of SCN9A and thus increases the ability of nociceptors to transmit a pain signal to the brain, making these people supersensitive to pain.

So it seems that mutations in SCN9A can cause extremely severe forms of altered pain sensation that are at two different ends of the spectrum. In between these extreme disorders, there is a wide variation in normal responses to pain We all have genetic variations i.e. slight differences in our genes, which make us code for slightly different proteins that in most cases are harmless but in some cases can lead to slightly different properties of the protein. Interestingly, researchers have identified and shown that variation in SCN9A are accountable for the range of pain sensitivity in normal individuals. So, not only can mutations in SCN9A cause terrible alterations to pain threshold, but they can also only slightly alter pain thresholds but not enough to cause disease. However, there are lots of other genes involved: NGF, NTRK1 to name a few.

From CIP and PE we know that SCN9A are key in pain sensation, and novel analgesics targeted to this protein are in the making, including the development of SCN9A blockers that prevent the transmission of pain signals from nociceptors to the brain. With the lessons learned from rare diseases such as CIP and PE we may be able to develop treatments for something much more common: chronic pain that affects up to 60% of people in the UK.

Rather than a simple switch that turns a light bulb on and off allowing us to sense pain, there is an intricate network of much more complicated dimmer switches and regulatory mechanisms which interconnect and affect the system, sometimes surprisingly. Pain signalling is vital and when something goes wrong, the fine tuning of events in this complex system are turned upside down and then and only then do we realise the gift and bliss of pain.