For years, researchers exploring chronic pain have focused mainly on neurons, the cells responsible for transmitting pain signals. That may not be the entire truth.

Several studies suggest that immune cells in the nervous system, such as microglia and astrocytes, play a significant role. These non-nerve cells can respond to threats like infections or toxins by releasing molecules that trigger inflammation in the nervous system.

While these responses are often helpful for healing, they can sometimes go overboard, leading to an ongoing inflammation that harms instead of heals.

Chronic pain is now suspected to be linked to these abnormal interactions between neurons and the cells of the immune system. While animal studies strongly support this idea, it remains unclear if the same happens in humans.

Evidence is limited to a few studies showing increased inflammation markers in the spinal cords of deceased chronic pain sufferers or in spinal fluid from patients with conditions like fibromyalgia. These findings are promising but cannot fully explain the role of neuroinflammation in live patients.

A Window Into Brain Inflammation
The translocator protein (TSPO) is a small protein located on the outer membrane of mitochondria, the power generator in our cells. The protein plays vital roles in cellular processes like cholesterol transport, stress response, and energy metabolism.

Though present in many cell types, TSPO levels are typically low in a healthy brain. However, during neuroinflammation, its levels spike, particularly in glial cells like microglia and astrocytes, making it a reliable marker for imaging brain inflammation.

This protein’s increased presence correlates with various conditions, such as multiple sclerosis, Alzheimer's disease, and pain-related disorders. In animal studies, for instance, TSPO rises significantly in glial cells following nerve injury, while neurons show little change. Such patterns suggest its value in understanding inflammation-driven diseases.

Imaging Chronic Pain with TSPO and PET
TSPO can be visualized in the living brain using positron emission tomography (PET) imaging.

Unlike other markers, TSPO can bind with high specificity to small, injectable molecules that light up on PET images. As these injectable molecules can pass the blood-brain barrier, the method can help detect subtle inflammatory signals in the brain and spinal cord.

In patients with chronic low back pain, PET imaging has revealed heightened TSPO activity in regions like the thalamus and sensory cortex, potentially linking neuroinflammation to pain.

Nociplastic pain refers to a type of pain caused by changes in the way the nervous system processes pain signals, even without clear tissue damage. It is thought to arise from alterations in the central nervous system, affecting how pain is perceived, intensified, or prolonged. Elevated TSPO levels have been associated with this specific pain type and related symptoms like depression. These findings suggest neuroimmune dysregulation may underlie both pain and mood disorders.

Beyond the brain, TSPO-PET imaging has detected inflammation in peripheral nervous system structures, such as spinal nerve roots and dorsal root ganglia, in patients with radiculopathy, sciatica being a well-known example. These signals align with pain severity and predict responses to anti-inflammatory treatments like steroid injections.

Neuroinflammation Across Chronic Pain Disorders
Research using TSPO imaging has revealed increased inflammatory signals in the central and peripheral nervous systems in various chronic pain conditions, including fibromyalgia, migraines, and complex regional pain syndrome.

Unlike chronic low back pain, where elevated TSPO levels are most prominent in a relatively small area, the deep brain structure thalamus. Fibromyalgia patients show widespread involvement of the cortex of the brain, particularly in regions like the prefrontal cortex, sensory areas, and parietal. These spatial differences in TSPO distribution seem to align with the specific pain characteristics of the two conditions, the former being localized the latter generalized.

In fibromyalgia, increased TSPO signals in somatosensory regions correlate with the body's pain map, while in migraines, signals correspond to the frequency of attacks and localize to areas representing the face. These findings suggest a disorder-specific distribution of neuroinflammation.

While TSPO imaging has expanded the understanding of neuroinflammation, its interpretation is complex. We do not know yet exactly what an elevated TSPO signal may reflect. Despite limitations, TSPO imaging holds promise as a tool for understanding and diagnosing chronic pain through the detection of inflammation across both the central and peripheral nervous systems.

In the future?
While promising, the field faces key questions: Can TSPO signals predict treatment outcomes or monitor therapy effects?

Large studies and clinical trials are underway to assess its potential as a diagnostic and precision medicine tool. Other imaging markers, including some targeting oxidative stress or inflammatory pathways, are being developed but remain less tested in pain research.

Emerging MRI methods may offer safer and more accessible alternatives for studying neuroinflammation. Techniques like diffusion MRI can detect changes linked to swelling, as seen in inflammation. Unlike PET, MRI avoids radiation exposure, allowing repeated use in clinical settings. These advancements could enhance understanding and management of pain through improved imaging approaches.

While still maturing, Imaging of inflammation in the brain holds the potential to refine treatment strategies and unravel chronic pain mechanisms.

About the scientific paper:

First author: Marco L. Loggia, USA
Published: Pain, November 2024
Link to paper: https://journals.lww.com/pain/fulltext/2024/11001/_neuroinflammation___does_it_have_a_role_in.8.aspx