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Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord

Joseph J Gallagher12, Maral Tajerian12, Tianzhi Guo3, Xiaoyou Shi12, Wenwu Li123, Ming Zheng2, Gary Peltz2, Wade S Kingery3 and J David Clark12*

Author Affiliations

1 Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA, 94304, USA

2 Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA, USA

3 Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

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Molecular Pain 2013, 9:40  doi:10.1186/1744-8069-9-40

Published: 8 August 2013



CRPS is a painful, debilitating, and often-chronic condition characterized by various sensory, motor, and vascular disturbances. Despite many years of study, current treatments are limited by our understanding of the underlying mechanisms. Little is known on the molecular level concerning changes in gene expression supporting the nociceptive sensitization commonly observed in CRPS limbs, or how those changes might evolve over time.


We used a well-characterized mouse tibial fracture/cast immobilization model of CRPS to study molecular, vascular and nociceptive changes. We observed that the acute (3 weeks after fracture) and chronic (7 weeks after fracture) phases of CRPS-like changes in our model were accompanied by unique alterations in spinal gene expression corresponding to distinct canonical pathways. For the acute phase, top regulated pathways were: chemokine signaling, glycogen degradation, and cAMP-mediated signaling; while for the chronic phase, the associated pathways were: coagulation system, granzyme A signaling, and aryl hydrocarbon receptor signaling. We then focused on the role of CcL2, a chemokine that we showed to be upregulated at the mRNA and protein levels in spinal cord tissue in our model. We confirmed its association with the nociceptive sensitization displayed in this model by demonstrating that the spinal but not peripheral administration of a CCR2 antagonist (RS504393) in CRPS animals could decrease mechanical allodynia. The spinal administration of CcL2 itself resulted in mechanical allodynia in control mice.


Our data provide a global look at the transcriptional changes in the spinal cord that accompany the acute and chronic phases of CRPS as modeled in mice. Furthermore, it follows up on one of the top-regulated genes coding for CcL2 and validates its role in regulating nociception in the fracture/cast model of CRPS.

Complex regional pain syndrome; CcL2; Chemokine; Chronic pain; Spinal cord; Microarray analysis; Transcriptome; Pathway analysis