Brain Neuroplastic Changes Accompany Anxiety and Memory Deficits in a Model of Complex Regional Pain Syndrome

Abstract

Background Complex regional pain syndrome (CRPS) is a painful condition with ~50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood. Methods We used a previously-characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n=8–20/group) observed in humans. Our central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus. Results We demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, we found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain derived neurotrophic factor in specific brain regions. Conclusions Our findings provide novel observations regarding behavioral changes and brain plasticity in a mouse model of CRPS. In addition to elucidating some of the supraspinal correlates of the syndrome, this work supports the potential use of therapeutic interventions that not only directly target sensory input and other peripheral mechanisms, but also attempt to ameliorate the broader pain experience by modifying its associated cognitive and emotional comorbidities.

Persistent, comorbid pain and anxiety can be uncoupled in a mouse model

“…In the present study, we observed that in the EPM test CFAinflammatory mice had a decreased open-arm and close-arm entry alternation and spent more time licking and favoring the affected paw. It has been reported that mice with chronic pain spend less time exploring novel objects in the novel-object recognition test [39,40]. Thus, attention toward the source or location of the pain may interrupt or ignore the aggressive behavior from aggressors in the SD stress process.…”

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

“…BDNF is a key signaling molecule involved in a wide range of central functions and neuronal plasticity, including modulatory actions in the hippocampus of relevance to learning, memory, neurogenesis, and mood control (89)(90)(91)(92)(93). Memory impairment after surgery has also been associated with reduced BDNF expression (94)(95)(96)(97). Conditional knockout of BDNF in the forebrain impairs hippocampal-dependent learning in mice (98,99).…”

The role of the extracellular matrix in chronic pain following injury

“…The mechanisms behind the chronification of pain are not clear with hypotheses ranging from dysregulated descending inhibitory pathways 35 to primary nociceptor plasticity 18 and altered central pain processing. 55 After injury, the ECM-neuron cross talk is particularly relevant because pain is associated with spinal plasticity, 20 including changes in dendritic architecture (dendritic length and branching and dendritic spine density and morphology) 46 that often rely on structural proteins. 48 These plastic changes could be maladaptive, resulting in central sensitization of second-order spinal neurons and, ultimately, the chronification of pain.…”