Introduction 

Central Pain Syndrome (CPS) is a chronic pain condition caused by damage or disease within the central nervous system (CNS), which includes the brain, the brainstem and the spinal cord. The underlying cause of CPS can be genetic or environmental, the latter including stroke, spinal cord injury, and multiple sclerosis, a condition characterised by neuroinflammation. The chronic pain experienced with CPS is mediated by central sensitisation, which is defined as an amplification of pain signals by the CNS in response to ordinary touch or mild stimulus.¹

Pain itself is a mechanism designed to protect a person from harm, and it can be triggered by inflammation. Inflammation is a defense mechanism that utilises immune cells and inflammatory mediators to address infections, disease, and injury, and it has been shown to interact with the sensory nervous system. Neuropathic pain, which affects the somatosensory nervous system, can result from an overactive immune response.² 

The involvement of neuroinflammation and glial cell activation as an underlying contributor to CPS is being increasingly uncovered, particularly in the context of central neuropathic pain following injury or in neuroinflammatory conditions. Understanding these mechanisms are essential in directing effective therapeutic interventions.² 

What is CPS?

CPS, which arises through chronic pain in response to damage within the CNS, is a condition accompanied by significantly impaired quality of life and debilitating pain. In addition to spontaneous or consistent pain, symptoms of CPS can include burning, tingling, and amplified responses to normally unpainful stimulation. Although the level of pain experienced is normally consistent, the wide range of causes of CPS lead to different levels of pain experienced by different people, the extent of which commonly relates to the cause of injury or damage. An individual's pain threshold, psychological state and underlying medical condition can also contribute to the level of pain.¹

CPS is commonly associated with neurological conditions, these include:^1,2,3

• Stroke: After a stroke, some individuals may develop CPS in response to neural pathway damage within the CNS
• Multiple sclerosis: This autoimmune neuroinflammatory condition is characterised by demyelination of nerves, which can affect normal pain pathways
• Spinal cord injury: Trauma or injury may trigger changes in the spinal cord which can lead to CPS

It is important to consider that chronic pain can significantly impact a person’s quality of life. It can be associated with increased risk of developing emotional distress, including depression and anxiety, sleep disturbances and cognitive impairments.¹

The role of neuroinflammation in CPS

Neuroinflammation

Neuroinflammation within the CNS is characterised by activation of resident brain immune cells, most importantly microglia and astrocytes. These glial cells make up 70% of the cells found in the CNS, and are activated in response to injury, infection or disease. Their activation leads to the release of inflammatory mediators, such as cytokines and chemokines. Neuroinflammation, in acute injury, serve as a protective mechanism, however, excessive and prolonged inflammation can be damaging and lead to changes in the nervous system. Studies show that the release of these inflammatory mediators by glial cells intensify pain signalling pathways and enhance neuronal excitability.^1,2,3,4

Glial cells

Glial cells, which include microglia, astrocytes, and oligodendrocytes, play a role in maintaining homeostasis in the CNS. After injury, these cells are activated and promote pain signalling. In the context of CPS, microglia and astrocytes are well studied.^5,6

Microglia are the brain resident macrophages in the CNS and are activated in response to nerve damage. Once activated, these cells change shape and migrate, producing inflammatory mediators including tumour necrosis factor alpha (TNFɑ) and interleukin-1b (IL-1b). These mediators intensify pain signaling by enhancing excitatory synaptic transmission. These cells also communicate with infiltrating immune cells, further sustaining inflammation and pain signalling.^5,6

Astrocytes are the dominant cell type in the CNS and play a role in maintaining homeostasis and supporting neuronal function. In response to injury or disease, astrocytes undergo reactive astrogliosis, the process by which they become activated. This leads to the release of inflammatory chemokines and cytokines including IL-1b, contributing to neuroinflammation. Interestingly, astrocytes and microglia communicate with each other in neuroinflammation, further amplifying the inflammatory response.^5,6,7

Central sensitisation 

Central sensitisation is a process by which neurones within the CNS are overresponsive to minimal input. The activation of glial cells, microglia and astrocytes, as well as neuroinflammation plays an essential role in the development of chronic pain through central sensitisation. Microglial cells in the spinal cord have been shown to increase excitatory activity in neurones whilst reducing inhibitory activity through the release of inflammatory mediators, enhancing pain transmission. Additionally, astrocytes have been shown to activate in response to nerve injury, altering neural excitability by modulating synaptic transmission, leading to chronic pain through central sensitisation. Changes in gene expression have also been reported following interactions between glial cells and neurones, contributing to chronic pain states.^1,3,5,8

Therapeutic approaches 

In most situations, CPS arises from an underlying chronic condition. Therefore, targeting the condition is an effective method to reduce the severity of pain experienced. In addition, studies have shown that patients respond well to neuromodulators. Antiepileptics have been suggested to reduce neuronal hyperexcitability and may therefore be used in patients with central post-stroke pain. Antidepressants have also been shown effective in CPS.^1,9

Considering the role of neuroinflammation and glial cell activation in CPS, targeting these processes have been investigated as a therapeutic strategy. Targeting chemokines and chemokine receptors that mediate neuroinflammation as well as the pain response have been suggested as potential strategies. Additionally, studies have investigated the potential of targeting downstream signalling pathways, such as the mitogen activated protein kinase pathway, that regulates neuroinflammation and central sensitisation associated with chronic pain. Although drugs targeting microglia or astrocytes are not currently approved to treat CPS, it is a promising strategy that warrants further investigation in this context.^10,11

Summary 

Central pain syndrome (CPS), which arises within the CNS, is a chronic pain condition. It is associated with impaired quality of life due to persistent and amplified responses to normally unpainful stimuli. CPS can be triggered by a wide range of causes, which include stroke, spinal cord injury, or multiple sclerosis. Moreover, neuroinflammation and glial cell activation play a role in CPS. Excessive inflammation within the CNS can be damaging and lead to neuronal changes, whilst microglia and astrocyte activation can lead to enhanced neuronal excitability. Both of these processes contribute to pain signalling, which is mediated by the release of inflammatory mediators and the process of central sensitisation; which is defined as an increased pain response to minimal input. Considering CPS commonly arises with an underlying condition, targeting the condition itself is an effective treatment. Nevertheless, neuroinflammation and glial cell activation have been implicated in CPS, thus targeting these processes and cells may lead to promising therapeutic strategies to improve overall quality of life and reduce chronic pain for those affected.. 

FAQs

What is the difference between central and peripheral pain syndrome?

Both syndromes are a type of chronic pain condition caused by damage to the nervous system. Central pain syndrome arises in response to damage within the CNS (ie. the brain and spinal cord), while peripheral pain syndrome originates from nerves outside of the CNS.¹

How is CPS diagnosed?

The diagnosis of CPS relies on symptoms persisting for at least 3 months. This includes oversensitivity to unpainful or minimally painful stimuli. In some cases, neuroimaging studies such as magnetic resonance imaging (MRI) may be used to identify underlying damage to the CNS.¹

Can central pain syndrome be cured?

Currently, there is no cure for central pain syndrome. Most treatment interventions focus on enhancing quality of life or addressing the underlying chronic condition. Treatment plans are therefore often individualised to the patient’s needs.¹