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 approximately 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: The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The 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: The authors 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, the authors 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: The study 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.

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Sphingosine 1-phosphate receptor modulation attenuate mechanical allodynia in mouse model of chronic complex regional pain syndrome by suppressing pathogenic astrocyte activation

Regional Anesthesia and Pain Medicine ◽

10.1136/rapm-2019-100801 ◽

2020 ◽

Vol 45 (3) ◽

pp. 230-238 ◽

Cited By ~ 2

Author(s):

Byung Joo Lee ◽

Jun Young Kim ◽

Hyung-jung Cho ◽

Donghwi Park

Keyword(s):

Mouse Model ◽

Complex Regional Pain Syndrome ◽

Mechanical Allodynia ◽

Pain Syndrome ◽

Lymphoid Tissues ◽

Astrocyte Activation ◽

Cast Immobilization ◽

Chronic Stage ◽

Receptor Modulation ◽

Sphingosine 1 Phosphate

Background and objectivesFTY720 ((2-amino-2-)2-[4-octylphenyl]ethyl)-1,3-propanediol) is an Food and Drug Administration (FDA)-approved immunomodulatory drug for treating multiple sclerosis. It inhibits lymphocyte egression from lymphoid tissues by downregulating sphingosine-1 phosphate receptor (S1PR). To date, there has been no study on the effects of FTY720 on the chronic stage of the complex regional pain syndrome (CRPS) rodent model, despite its antiallodynic effect in previous studies. Thus, the aim of this study is to investigate the effect of FTY720 in a chronic stage of the CRPS mouse model.MethodThe authors used a mouse model of CRPS, involving tibia fracture/cast immobilization, to test the efficacy of intrathecal FTY720 (2.5 or 25 ng daily; 6 days) or vehicle during the chronic (7 weeks after fracture) stage of CRPS.ResultsIntrathecal recombinant FTY720 administration was antiallodynic in the chronic stage of the CRPS mouse model, and such an effect of FTY720 developed by modulating astrocyte activation in the spinal cord. Additionally, according to the in vitro data, the FTY720 treatment inhibited S1P-induced increase in the nitric oxide production and suppression of the NF-κB pathway, by inhibiting the phosphorylation of NF-κB/p65 in astrocytes without toxic effect on astrocytes.ConclusionCollectively, these results demonstrate that intrathecally administered FTY720 attenuates mechanical allodynia in the chronic stage of the CRPS mouse model.

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Experimental Forearm Immobilization in Humans Induces Cold and Mechanical Hyperalgesia

Anesthesiology ◽

10.1097/aln.0b013e31817f4c9d ◽

2008 ◽

Vol 109 (2) ◽

pp. 297-307 ◽

Cited By ~ 85

Author(s):

Astrid J. Terkelsen ◽

Flemming W. Bach ◽

Troels S. Jensen

Keyword(s):

Skin Temperature ◽

Complex Regional Pain Syndrome ◽

Healthy Subjects ◽

Pain Threshold ◽

Pain Syndrome ◽

Unknown Etiology ◽

Cast Immobilization ◽

Painful Condition ◽

Skin Fold ◽

Pressure Pain Thresholds

Background Complex regional pain syndrome is a painful condition of unknown etiology. Clinical and experimental observations suggest that limb immobilization may induce symptoms and signs characteristic of complex regional pain syndrome. This study examined the effect of forearm immobilization on regional sensory and autonomic functions in healthy subjects. Methods Thermal and mechanical sensitivity, skin temperature, and vasoconstrictor responses were measured in 30 healthy subjects before and 0, 3, and 28 days after scaphoid cast immobilization. Fifteen subjects served as nonimmobilized controls. Results At cast removal, 27 subjects experienced pain at joint movement. Cast immobilization induced cold hyperalgesia in glabrous and hairy skin on the immobilized hand and induced significant skin temperature differences between the control and the immobilized hand at cast removal and after 3 days. Immobilization also reduced pain threshold at skin fold testing at all time points after cast removal. All measures except pain threshold at skin fold testing were normalized after 28 days. Immobilization did not affect thermal detection, heat pain, and pressure pain thresholds; resting skin perfusion; or vasoconstrictor responses induced by mental stress or deep inspirations. Conclusions Four weeks of forearm immobilization caused transient changes in skin temperature, mechanosensitivity, and thermosensitivity, without alteration in the sympathetically mediated vascular tone.

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Manual Therapy Reduces Pain Behavior and Oxidative Stress in a Murine Model of Complex Regional Pain Syndrome Type I

Brain Sciences ◽

10.3390/brainsci9080197 ◽

2019 ◽

Vol 9 (8) ◽

pp. 197 ◽

Cited By ~ 5

Author(s):

Afonso S. I. Salgado ◽

Juliana Stramosk ◽

Daniela D. Ludtke ◽

Ana C. C. Kuci ◽

Daiana C. Salm ◽

...

Keyword(s):

Oxidative Stress ◽

Complex Regional Pain Syndrome ◽

Manual Therapy ◽

Pain Syndrome ◽

Pain Behavior ◽

Protein Carbonyls ◽

Type I ◽

Syndrome Type ◽

Painful Condition ◽

And Oxidative Stress

Complex regional pain syndrome type I (CRPS-I) is a chronic painful condition. We investigated whether manual therapy (MT), in a chronic post-ischemia pain (CPIP) model, is capable of reducing pain behavior and oxidative stress. Male Swiss mice were subjected to ischemia-reperfusion (IR) to mimic CRPS-I. Animals received ankle joint mobilization 48h after the IR procedure, and response to mechanical stimuli was evaluated. For biochemical analyses, mitochondrial function as well as oxidative stress thiobarbituric acid reactive substances (TBARS), protein carbonyls, antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) levels were determined. IR induced mechanical hyperalgesia which was subsequently reduced by acute MT treatment. The concentrations of oxidative stress parameters were increased following IR with MT treatment preventing these increases in malondialdehyde (MDA) and carbonyls protein. IR diminished the levels of SOD and CAT activity and MT treatment prevented this decrease in CAT but not in SOD activity. IR also diminished mitochondrial complex activity, and MT treatment was ineffective in preventing this decrease. In conclusion, repeated sessions of MT resulted in antihyperalgesic effects mediated, at least partially, through the prevention of an increase of MDA and protein carbonyls levels and an improvement in the antioxidant defense system.

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