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Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients

Albrecht, Daniel, S.a,b; Ahmed, Shihab, U.c; Kettner, Norman, W.d; Borra, Ronald, J.H.e,f; Cohen-Adad, Julieng,h; Deng, Haoi; Houle, Timothy, T.i; Opalacz, Arissac; Roth, Sarah, A.c; Melo, Marcos F., Vidali; Chen, Lucyc; Mao, Jianrenc; Hooker, Jacob, M.a; Loggia, Marco, L.a; Zhang, Yic,*

doi: 10.1097/j.pain.0000000000001171
Research Paper

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, 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 with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, 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 with 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 with more superior segments). Furthermore, the neuroforaminal translocator protein 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.

Here, we show that patients with lumbar radiculopathy exhibit elevated levels of the 18 kDa translocator protein, a marker of neuroinflammation, in both the neuroforamina and spinal cord, implicating spinal neuroinflammation in chronic pain pathology.

aDepartment of Radiology, A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

bDepartment of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

cDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

dDepartment of Radiology, Logan University, Chesterfield, MO, USA

eMedical Imaging Centre of Southwest Finland, Department of Diagnostic Radiology, Turku University Hospital, Turku, Finland

fDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

gDepartment of Electrical Engineering, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada

hFunctional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, QC, Canada

iDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Corresponding author. Address: MGH Center for Pain Management, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA. Tel.: (617) 643-9308. E-mail address: yzhang20@partners.org (Y. Zhang).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

M. L. Loggia and Y. Zhang are co-senior authors and contributed equally.

Received October 12, 2017

Received in revised form January 18, 2018

Accepted January 24, 2018

© 2018 International Association for the Study of Pain
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