Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (e.g., microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared to healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18kDa translocator protein (TSPO), in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients’ clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared to both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared to more superior segments). Furthermore, the neuroforaminal TSPO signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.
1A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129.
2Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114.
3MGH Translational Pain Research Center, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114.
4Department of Radiology, Logan University, Chesterfield, MO, 63017.
5Medical Imaging Centre of Southwest Finland, Turku University Hospital, Turku, Finland; Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
6Department of Electrical Engineering, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada; Functional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, Quebec, Canada.
7Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114.
Corresponding authors: Marco L. Loggia, PhD Massachusetts General Hospital, A. A. Martinos Center for Biomedical Imaging 149 Thirteenth Street, Room 2301, Charlestown, MA 02129 Phone: (617) 643-7267 Email: firstname.lastname@example.org
Yi Zhang, MD, PhD Massachusetts General Hospital, Center for Pain Medicine 15 Parkman Street, Boston, MA 02114 Phone: (617) 726-8810 Email: email@example.com
* Equal contribution, co-senior authors