In animal models of pain, microglia and astrocytes become `activated' and start releasing pro- inflammatory cytokines and other products that further sensitize pain pathways. Thus, it is generally believed that glial cells actively contribute to the pathophysiology of persistent pain. Despite hundreds of studies with laboratory models, it is currently unclear whether glial cells have a role in human pain. Recently, however, our group has demonstrated that patients with chronic low back pain (cLBP) have increased brain levels of the 18kDa translocator protein (TSPO). In addition, preliminary data collected from a different cohort of cLBP patients suggest an increase in spinal cord TSPO levels as well. As TSPO upregulation is a marker of glial activation, these observations support a role for glial activation in human chronic pain. With the current proposal, which builds logically on our prior observations, we will compare spinal and brain glial activation in healthy volunteers, and patients with subacute (i.e., pain duration between 1 and 3 months) and chronic (i.e., pain duration > 1 year) low back pain. Scans will be performed with integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and [11C]PBR28, a second- generation radioligand for TSPO, with an excellent ratio of specific-to-nonspecific binding. By comparing [11C]PBR28 scans in cLBP patients of different clinical presentation (i.e., with radicular pain vs axial pain) we will test the hypothesis that glial activation in the primary somatosensory/motor cortices follows a somatotopic organization that mirrors the somatic distribution of the patients' symptoms. Moreover, we will perform cross- sectional comparisons between subacute and chronic low back pain, as well as longitudinal studies of subacute low back pain patients across time, to capture the transition to chronic pain, or the return to pain-free status. These investigations will allow us to assess the temporal evolution of glial activation in humans with pain disorders. A subset of sLBP patients will be re-scanned after a 2-week treatment with either minocycline (which was recently found to reduce sLBP) or placebo. While minocycline is a known glial inhibitor in animal models, the mechanisms underlying its effect on human pain are unknown. Finally, we will compare the baseline status of glial activation in subacute patients that have subsequently transitioned to chronic pain, or have healed. This comparison will allow us to test the hypothesis that glial activation can predict transition from subacute to chronic pain. While this project is purposely focused on a specific condition (low back pain), the identification of a role of glia in the development and maintenance of persistent pain and pain-related disability will have important practical implications for the management of a wide range of pain disorders.

Public Health Relevance

Despite the results from hundreds of studies with laboratory animals, it is currently unclear whether glial cells have a role in human pain. In this project, we will use PET/MR imaging to image brain and spinal glial activation in patients with subacute and chronic low back pain, and the effects of its pharmacological modulation. The identification of a role for glia in the development and/or maintenance of persistent pain will have important practical implications for the management of pain, and the development of tailored preventive interventions focused on glial modulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Mohapatra, Durga Prasanna
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Massachusetts General Hospital
United States
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