Pain genes and perception

02 August 2011
Posted by Katrina Stewart.

At some point in their lives, most people will have found themselves wishing that they could not feel pain. After all, how can such an unpleasant sensation be helpful? A quick look at life without pain, however, is a brutal reminder of how lucky we are to have it.

"I've broken almost every single bone in my body ... When you've got no fear of being hurt at the end of it, then there's nothing to stop Steve Peteyou from doing it."

Paul Waters from the UK and Steven Pete from the USA, along with some of their siblings, suffer from 'congenital insensitivity to pain'. This is a genetic condition that causes a complete lack of pain from birth, even though their sense of touch is still intact. This is incredibly rare. But it is a clear illustration of why pain is so important, and has given us an insight into which proteins and pathways are necessary to feel pain.

Their condition brought them together when they were 4 and 8 years old. Their parents made contact to share experiences of rearing children unable to feel pain. Imagine the challenge of protecting babies and toddlers who bite off their fingers and tongues, enjoy the sizzling sound when their hand touches the hob, and like the feeling of vibration when they bash their heads against walls.

Paul and Steve were diagnosed as young children. Paul's parents noticed that he failed to respond when they accidentally jabbed him with nappy pins or trod on him, and Steve's parents were horrified when they discovered he had bitten off a chunk of his own tongue.

Paul remembers the risks that he would take. "I would do things as a child that other children just wouldn't even dream of ... me and my sister used to jump down the stairs together. We'd land at the bottom of the stairs, breaking both our legs. And the reason why we did it was because both of us, at the time, enjoyed the sensation of being in mid-air."

As they grew up, Paul and Steve had to learn how to spot their injuries so their bones could be re-set and their infections treated. Now, they recognise the rush of adrenaline, and look for the signature signs of heat and swelling that indicate an injury.

"If I was to break a bone, I wouldn't feel the pain of it, but I would feel a clicking and crunching. I'd know it was broken, because you'd have movement there that just shouldn't be there" explains Paul.

But the injuries that they sustained as children are catching up with them now that Paul and Steve are in their 20s. As Steve describes, "I'm not going to have the kind of life that I've always had being younger. I'm going to have mobility issues ... I'm going to more than likely lose my left leg due to the joint issues in my knee. But that has always been in the back of my mind, since I was 13 or 14."

Steven Pete and Paul Waters describe what it is like to have no pain sensation.

Dr Geoffrey Woods, a clinical geneticist from the University of Cambridge, sees many people like Paul and Steve. "You can see that treating someone who has excess pain is obvious, but actually treating someone who doesn't feel pain is also just as important."

But what kinds of genes are damaged to cause this disastrous deficit in pain? The perception of pain is a complex process, and mutations could potentially disrupt it at any point along the way.

The genetic culprits for pain syndromes

In order to feel pain, pain-sensing nerves, or nociceptors, have to be activated. They fire signals to the spinal cord, which are relayed to various parts of the brain. Professor John Wood, from University College London, has spent much of his career hunting down the genes that encode the proteins involved in pain sensation.

"It's possible to screen large numbers of people with unusual pain syndromes and home in on the genes that are responsible for changing pain thresholds and pain sensations." he explains.

Through experiments such as these, scientists have found two main types of genes encoding proteins important in pain. Firstly, there are the proteins needed for the development and survival of pain-sensing nerves.

"During development, the number of nerve cells that are made is dependent upon various factors, so called tropic-factors. So if you have any deficits in that kind of signalling mechanism, then you tend to have the wrong number of nerve cells and that can cause the loss of cells and the loss of pain."

For example, Nerve Growth Factors (NGFs) control the development and survival of nerve cells. A Swedish family who have many members who are insensitive to pain have been found to have a mutation in an NGF gene which means that their nociceptive nerves do not develop properly.

Apart from trophic factors like NGF, there are also proteins that control the activity rather than number of nociceptors. As John Wood explains, these proteins could be targeted to produce pain relieving drugs, temporarily mimicking conditions like congenital insensitivity to pain.

"It's basically an electrical signalling system so anything that's responsible for changing the sensitivity of nerve cells involved in pain processes is a potential drug target."

This second group of genes includes those that code for structures called ion channels.

Ion channels: the gatekeepers of pain

Stimuli like heat and pressure, or chemicals like capsaicin, the spicy ingredient in chilli, cause pain by activating ion channels. Shaped like miniature doughnuts, they form pores in the membranes of cells and regulate the electric activity of nerve cells by permitting certain types of charged particles, or ions, to pass through.

Cell Membrane Ion Channel MosaicThe group of channels that let positive sodium ions through are particularly important. When a nerve cell is inactive these channels are closed and the voltage inside the cell is negative compared to the outside. But when there is a signal, like a pinprick to the skin, the membrane of the cell depolarises, meaning that the inside begins to become more positive than normal. If the internal voltage within the cell departs from normal by more than a critical amount, so called "voltage-sensitive" sodium channels pick up on this change and activate themselves, admitting more positively-charged sodium ions. This amplifies the depolarisation process and triggers the generation of an electrical impulse known as an action potential, which travels along the nerve conveying the information to the brain.

Geoffrey Woods discovered one such voltage-sensitive sodium channel, called NaV1.7, which is involved in this process and encoded by a gene called SCN9A.

"We discovered the SCN9A gene's importance in pain by studying three Pakistani families where there were children who felt no pain whatsoever ... You have 2 copies of SCN9A. We found that you have to have both copies of SCN9A completely de-activated, and when that occurred you had no pain sensation at all."

There are many types of nerve cell. Some sense touch, some temperature, others detect itch sensations and there are several types of pain-sensing nerves. But what is interesting about the sodium channel discovered by Woods and encoded by the SCN9A gene is that its presence is absolutely critical for pain nerves to be able to produce action potentials. It is not, however, needed by other non-pain nerves conveying sensations like fine touch. So, when an individual has no functioning SCN9A genes, they can still feel everything apart from pain.

"Pain is perceived by different receptors in your body, so cold pain is perceived differently to burning pain is perceived differently to pressure pain to fracture pain etc. But all of these different ways of perceiving pain seem somehow to have SCN9A, so SCN9A must be some kind of common amplifier for pain perception," says Woods.

A separate group of scientists studied a 9 year old girl who had partial insensitivity to pain. They found that she had mutations in both of her SCN9A genes although, surprisingly, she could still feel some pain in extreme situations. For example she did not complain when, as a 2 year old, she suffered a second degree burn of her hand. But a severe ear infection that burst her ear drum caused her to complain briefly of pain for the first time in her life. Scientists speculate that the mutations in her SCN9A genes cause her NaV1.7 sodium channel to be defective, but not completely destroyed - perhaps an enviable situation to be in, as she seems to feel enough pain to keep herself out of trouble, but not enough to feel the unpleasant side effects on a day to day basis!

If mutations that inactivate the NaV1.7 sodium channel cause a lack of pain, then it makes sense that mutations that cause the channel to be over-active would cause excess pain.

Dr Geoffrey Woods explains how the SCN9A gene may determine pain thresholds.

"There's been studies on two conditions, one's called congenital erythmalgia. The second condition was called paroxysmal extreme pain disorder. The distribution of pain is different, the age of onset is different, but they're both caused by mutations in the SCN9A gene. And they seem to have slightly different mechanisms of keeping the pain channel open, or hyperactive," Woods explains.

From rare to regular - does everyone feel pain differently?

So we've established that rare mutations can have a dramatic effect on pain sensation. But what about more common and subtle variations in our genetic code? After finding the rare pain syndromes associated with SCN9A, now Woods wants to find out about more common variations in the SCN9A gene.

"We just wondered whether we would find that changes in SCN9A which were in the general population affected the degree of pain that people felt."

So he and his team have been looking at groups of patients with common causes of pain such as backache, osteoarthritis, or post-mastectomy pain.

"For each case we had a cohort of patients who were very well characterised for how much pain they had suffered, and there was DNA stored. We then used our biggest cohort and looked through the SCN9A gene at 30 changes that were known to occur, and found that one particular change which altered one amino acid seemed to be clearly associated with those people who felt the most pain."

About 1-3% of people have two copies of this version, or allele, of SCN9A which causes the most pain.

"The effect was clear-cut, but not huge. It maybe contributed to 10-20% of the pain they felt, and certainly suggested very strongly that SCN9A was one of the factors responsible for people's pain threshold."

And there are lots of other single letter genetic variants or polymorphisms in other genes that have been found to influence the sensation of pain. These include another group of ion channel genes called the transient receptor potential (TRP) channels. For example, in the TRPV1 gene, which encodes a receptor for extreme heat and the capsaicin from chillies, there is a variant conferring decreased pain sensitivity - perhaps explaining why some can chew on chillies and feel less of the burning pain that overcomes most of us.

And it's not just ion channels genes that can have these pain-altering SNP

Catechol-O-methyltransferase (COMT) is an enzyme that breaks down and deactivates catecholamines, chemicals that include the fight-or-flight hormone, adrenaline, and neurotransmitters like noradrenaline and dopamine that nerve cells release in order to communicate. Polymorphisms in the gene for CO

See our podcast, '
Pushing back the pain barrier', to find out more about how current and future pain killers may work.

cause the enzyme to have a reduced activity, leading to a build-up of catecholamines. For reasons not fully understood, this seems to increase pain sensitivity. There are even variations in our genetic code that alter the effectiveness of pain killers and polymorphisms in the opioid receptor, 'μ1', render opiate drugs like morphine much less effective.


So, it is quite possible that those who complain of more pain for a given injury can legitimately blame a crop of gene variations in their genomes, paper-cuts, which are always agony, excluded! However, as John Wood points out, genetics is never going to entirely explain away the variation in how different people report pain because the environment we grow up in moulds our personalities and pain thresholds. Papercut

However, it's obvious from a brief conversation with Paul and Steve that abolishing pain is not a good idea.

"What we really want is to normalise pain thresholds to get people to have normal sensations of pain rather than blocking it completely. And that is probably a feasible objective for 95% of pain conditions in the next 20 or 30 years, given the knowledge that we've presently got."

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