Headache, heartburn, sprained ankle, or a cut on your finger. Everyone experiences pain at some point in their lives. It can be bearable or severe, but the thought that it will go away is comforting. But what if it will not go away? If the pain stays with someone day and night without any explanation? People with Central Pain Syndrome have to live with constant pain in their bodies. This condition originates from their nervous system when brain regions and nerve cells do not function properly.

What is central pain syndrome?

“You're at war with your body, the body is, and the mind, and it's conflicting, it's always conflicting.”¹ This is an impression of how a person with Central Pain Syndrome can experience their daily life. Central Pain Syndrome (CPS) is a terrifying condition in which you constantly feel pain without any physical cause, but because of a problem in the nervous system. The reasons could be a brain or spinal cord injury, or chronic conditions like multiple sclerosis (full list is available here). 

The characteristics of CPS pain vary in location, intensity, and prevalence. You usually experience moderate to severe pain, which can worsen due to other factors, such as cold weather, stress, or physical activity. The pain sensation differs from person to person, ranging from burning, stabbing, severe itching, painful numbness, aching, intense pressure, to cutting. Overall, 7 million people live with CPS, a condition that cannot even be eased with strong painkillers. 

But how can this condition develop? To identify potential issues, we first need to understand the normal pain processing.

Overview of normal pain processing

You’re baking at home, and when you try to remove your dinner from the oven, you accidentally touch the 180°C oven wall. You immediately feel a sharp pain in your hand and pull it away. But what is happening in your nervous system when you experience this burning sensation? 

Ascending pathways

When something hurts, ascending pathways get activated.² In this process, the pain signal travels from the body up to the brain. This pathway starts with the nociceptors, which are specialised sensory structures in your skin, waiting for a harmful signal. If you burn your skin, the sensation switches the nociceptors on, and they send a pain stimulus through neurons.

This signal enters through a structure in the spinal cord called the dorsal horn. This structure is responsible for carrying different sensory signals to the brain. In the dorsal horn, the activation of the neurons by receiving the pain signal releases different neurotransmitters. These chemical compounds are like postmen: they serve as messengers for nerve cells, carry information, and help their communication. In this case, one of the neurotransmitters is glutamate, which serves as an excitatory messenger that helps with the quick signalling of pain.

The pain signal is still in the dorsal horn, when an interesting thing happens. From one side of the dorsal horn, the neurons cross to the other side, meaning that if you experience a burn on your right hand, the pain signal will travel from the left side of your spinal cord to the left side of your brain. This is why brain injury on one side of the brain causes pain sensation on the opposite side of the body.

After the cross-over, the stimulus (pain signal) reaches the spinothalamic tract and starts its travel to the brain, where it first reaches the thalamus. This region's duty is similar to a relay station: it sends the incoming signals to specific parts of the brain. In this case, it transfers the pain signal to the somatosensory cortex. When the pain signal reaches this part of the brain, it helps you locate the specific pain, process its intensity, and type — in this case, a bad burn on your right hand.²

But there is another pathway that controls the pain sensation.

The ascending pathways (Created in https://BioRender.com)

Descending pathways

After the burning sensation reaches the brain, another system starts working: the descending pathways.² This system controls the pain volume by modulating (amplifying or inhibiting) the signal from the brain down to the spinal cord. Without this system, pain would be much more intense and harder to manage.

When the pain stimulus reaches the brain, with the involvement of multiple brain regions, it evaluates how to respond. It takes into account different aspects: the pain’s location, intensity, emotional response, and memories. Based on this information, the periaqueductal grey decides whether to amplify the pain in order to protect the body or suppress it to help escape a life-threatening situation.

The final decision is sent to the `Rostral Ventromedial Medulla (RVM), which is responsible for transferring the signal to the spinal cord.² The RVM has two types of cells: ON-cells and OFF-cells. ON-cells are responsible for facilitating the pain by amplifying pain signals going up to the brain, while OFF-cells help to suppress harmful signals and decrease the pain.³ These cells send a descending signal from the brain to the dorsal horn of the spinal cord.²

In the dorsal horn, inhibitory neurotransmitters are released. These chemical messengers serve to suppress the function of the neurons of the ascending pathways. In other words, they try to prevent the pain signal from going back up to the brain. Important inhibitory neurotransmitters are serotonin and Gamma-Aminobutyric Acid (GABA). Due to their release, fewer pain signals travel back to the brain, which eventually leads to the ease of pain, and the burning sensation in your hand eventually fades away.²

The descending pathways (Created in https://BioRender.com)

Disruptions in pain processing in central pain syndrome

In case of CPS, different parts of the brain and the pain processing pathways can malfunction due to damage in the nervous system. In the following, we will go through possible explanations for the disrupted pain mechanism.⁴ These are not always confirmed by studies involving people with CPS, but by animal studies and other findings inferred from closely related pain research.

Harmful changes in brain regions

After a brain or spinal cord injury (like a stroke or lesion), the nervous system tries to heal itself. But instead of helpful changes, the rewiring process can go sideways, become unorganised, and create or amplify pain. This is called maladaptive (harmful) reorganisation in the brain function and structure, and can involve mainly two parts of the brain: the thalamus and the cortex. 

Thalamus reorganisation

As previously mentioned, the thalamus plays an important role in normal pain processing. But sometimes after an injury or illness, the affected area no longer functions properly.⁵ When injury happens in the spinothalamic tract, it can lead to disrupted or distorted signal transfer from the spinal cord to the thalamus. This can lead to hyperalgesia or allodynia. 

In hyperalgesia, the disruption exaggerates pain sensations, making them more intense; a tiny cut feels like a very deep one. In allodynia, a harmless stimulus, like wearing clothes, can be a painful experience. In a third case, the signal disruption can generate ‘ghost’ signals, aching and pain, when there is no apparent reason for them.

The role of the thalamus as a ‘relay station’ can also be affected. Because it serves as a signal transmitter, the body needs to be able to turn the pain transmission off when needed. But when an injury occurs, this function can be destroyed. It is called disinhibition when the thalamus cannot understand a ‘stop’ signal and remains constantly active, creating or exaggerating the pain signal.⁶

Cortical sensitisation

Due to a stroke or injury, changes in the cortex structure and function can lead to enhanced, constant pain experiences, which is called cortical sensitisation. In this process, the neurons become hypersensitive and/or hyperactive to different stimuli. Cortical sensation can also cause hyperalgesia and allodynia, where you may feel that a hug or a pat is hurtful, or a touch of a heavy blanket as a painful pressure. A third phenomenon is global sensory hyperresponsiveness, which causes an extreme response to external and internal stimuli. You might find bright lights, loud noises, or smells irritating, and might even be disturbed by your own heartbeat or bowel movement.⁷

Imbalance in neurotransmitters

Glutamate is a neurotransmitter that keeps the neurons active and amplifies the pain signal. But too much of it causes a problem, and can lead to constantly active neurons, and amplified pain sensation.⁶ 

GABA has a major role in the inhibition of pain processing. When GABA is released from one neuron, it quickly binds to the neighbouring neuron and reduces its ability to receive, create, or send neurotransmitters to other nerve cells. But their role can be tempered, too. After an injury, GABA production and activity can be reduced, and without their inhibiting role, the dorsal horn neurons remain activated, causing a constant or exaggerated pain experience.⁶ 

Glial cell activation 

Neuroglial cells are different from nerve cells, but are also part of the nervous system. They are generally smaller cells, but they outnumber neurons. They have an essential role in maintaining the environment of the nerve cells, controlling the signalling, and helping the neural development. 

A type of glia, the microglia, acts as an immune cell for the nervous system. Microglial cells release cytokines, which are small protein molecules that help regulate an inflammatory response. But these normally supportive microglial cells can become hyperactive after an injury. This can lead to an increase in the number of inflammatory cytokines, such as tumour necrosis factor-alpha (TNFα), interleukin-1beta (IL-1β), and brain-derived neurotrophic factor (BDNF). which  can amplify the pain signal and increase the pain sensation ^8,9  

Summary

Central pain syndrome affects 7 million people in the world, causing constant pain sensations due to damage to the nervous system. Although the exact causes are still not entirely known, animal studies and pain research can provide an answer to what kind of disruptions in the normal pain processing system can lead to CPS. These include harmful changes in different brain regions, an imbalance in the neurotransmitters, and glial cell activation. Understanding the reasons behind CPS can help find better treatment for this condition.