Microglial Activation in Nociplastic Pain: From Preclinical Models to PET Neuroimaging and Implications for Targeted Therapeutic Strategies

Nociplastic pain has recently been introduced as a third entity for identifying patients suffering from chronic pain that arises from altered nociception, without evidence of peripheral nociceptors activation or alterations of the somatosensory system. Currently, the main challenge of nociplastic pain is that it remains a diagnosis of exclusion, since no specific biomarkers are available. Positron emission tomography (PET) neuroimaging studies, using selective translocator protein (TSPO) radiopharmaceuticals, specific for microglia activation, showed a strong correlation between neuroinflammation and nociplastic pain: in particular, in fibromyalgia (FM), which is the prototype disease. Neuroimaging studies identified key brain changes associated with pain processing and neuroinflammation in patients suffering from widespread pain, often associated with sleep, mood disorders, and cognitive impairment. The present review will provide an overview on the role of neuroinflammation in nociplastic pain, focusing on preclinical evidence of microglia activation and advances in PET neuroimaging. Understanding the role of neuroinflammation could have relevant implications in selecting targeted therapeutic strategies and improving analgesic efficacy.