Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse modelResearch in context
Emerson Krock,
Magali Millecamps,
Kathleen M. Anderson,
Akanksha Srivastava,
Troy E. Reihsen,
Pawan Hari,
Yue Ran Sun,
Seon Ho Jang,
George L. Wilcox,
Kumar G. Belani,
David S. Beebe,
Jean Ouellet,
Manuel R. Pinto,
Lois J. Kehl,
Lisbet Haglund,
Laura S. Stone
Affiliations
Emerson Krock
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada
Magali Millecamps
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada
Kathleen M. Anderson
Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN 55455, USA
Akanksha Srivastava
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada
Troy E. Reihsen
Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA
Pawan Hari
Department of Epidemiology, University of Minnesota, Minneapolis, MN 55455, USA
Yue Ran Sun
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada
Seon Ho Jang
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada
George L. Wilcox
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
Kumar G. Belani
Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA
David S. Beebe
Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA
Jean Ouellet
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada; Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Quebec H4A 0A9, Canada
Manuel R. Pinto
Twin Cities Spine Center, Minneapolis, MN 55404, USA
Lois J. Kehl
Minnesota Head & Neck Pain Clinic, St. Paul, MN 55114, USA
Lisbet Haglund
McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Surgery, Orthopaedic Research Lab, McGill University, Montreal, Quebec H3A 1G1, Canada; Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Quebec H4A 0A9, Canada
Laura S. Stone
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0G1, Canada; McGill Scoliosis and Spine Research Group, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Anesthesia Research Unit, Montreal, Montreal, Quebec H3A 1G1, Canada; Faculty of Medicine, Department of Pharmacology and Therapeutics, Montreal, Quebec H3A 1G1, Canada; Corresponding author at: Alan Edwards Centre for Research on Pain, Faculty of Dentistry, McGill University, 740 Docteur Penfield Ave, Suite 3200, Montreal, Quebec, Canada.
Background: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. Methods: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs.The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. Findings: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. Interpretation: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. Fund: Supported by NIH, MMF, CIHR and FRQS. Keywords: Intervertebral disc degeneration, CXCL1, CXCL5, Cerebrospinal fluid, CXCR1/2, Reparixin
