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What causes chronic pain? Microglia might be to blame

Chronic pain occurs when nerve cells misfire and send faulty pain signals to the brain. pinkangelbabe

Imagine that a soft touch or brush of the skin was enough to evoke excruciating pain. This experience is common among people who suffer with chronic pain from nerve damage. The causes are varied and include diseases such as diabetes, multiple sclerosis and AIDS, as well as tumours, stroke, complex regional pain syndrome and traumatic injury from serious accidents.

One in five Australians live with chronic pain. And the impact on the lives of sufferers is enormous: it interferes with the ability to work, perform daily activities, get a good night’s sleep and even maintain relationships. On top of these human costs, chronic pain costs the Australian economy $34.3bn each year.

Signalling pain

Normally, pain serves a protective role. It’s felt when nerve endings sense the body is in danger and send pain signals, via nerve cells, to the spinal cord and brain. Chronic pain occurs when something in this complex system goes wrong, and nerve cells misfire and send faulty pain signals to the brain.

Scientists now believe that the activation of microglia cells in the central nervous system is the driving force behind chronic pain. Interestingly, these cells can act in two opposing ways; one is beneficial to the body, the other is detrimental.

Good microglial activation

Microglia, under normal circumstances, serve an important role. They make up the immune system of the central nervous system and are known as “sensors of pathology”. They forage the central nervous system for damaged nerve cells, plaques, and infectious agents. When they encounter such nastiness, they switch on – or become activated – and fight against it.

Microglia also communicate with nerve cells by releasing signalling substances that promote nerve cell regeneration. This generally helps to fight central nervous system immune challenges and protect nerve cells.

Bad microglial activation

These activated good guys can turn very bad – and this process of “going bad” affects the functioning of the central nervous system and contributes to chronic pain. We’re still unsure what makes microglia harmful but it’s likely due to the way microglia are activated.

Microglial activation in those with chronic pain is a complex phenomenon. Damaged nerve cells send out signals, in the form of chemical substances (including ATP and fractalkine), which are picked up by receptors on microglia and cause microglial activation. Studies have shown that activation of microglia requires the activation of microglial P2X4 and P2X7 receptors. Mice without these receptors don’t develop chronic pain. It is likely that blocking these receptors in humans leads to similar results.

Once the receptors are activated, they cause microglia to activate and produce a variety of cytokines – harmful inflammatory molecules that cause pain sensations and in turn act on damaged nerve cells. This makes nerve cell damage worse, causes more pain and leads to more microglial activation. And this painful response loop continues long after any physical injury is healed. The result: chronic pain.

Activated microglia expressing green fluorescent protein. Activation of microglia can be beneficial or harmful, depending on the conditions under which activation occurs. Gerry Shaw

Microglial substances increase pain transmission by over-exciting nerve cells, and causing inflammation. This amplifies the pain message and increases chronic pain.

Two key cytokines released from microglia (which are thought to have a detrimental effect on health) are interleukin-1beta and tumour necrosis factor- alpha. These substances activate p38 MAP kinase, which regulates the pain response and are toxic to nerve cells. In some cases, they can even can cause nerve cell death.

Scientists have found that blocking microglial activation in mice with chronic pain reduces harmful cytokines. In time, scientists may be able to stop nerve cells from over-firing in humans, which will reduce the pain response and help alleviate symptoms of chronic pain.

Next steps

The ability to block harmful microglia cells represents an exciting opportunity for treating chronic pain. But first, scientists need to better understand how chronic pain develops and what determines whether microglial activation will be beneficial or harmful.

Understanding the complex relationship between microglia and nerve cells will allow scientists to develop new medications to provide relief to those suffering from chronic pain.

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