Pathophysiology of complex regional pain syndrome

Schwartzman, Robert J.; Alexander, Guillermo M.; Grothusen, John R.

doi:10.1586/14737175.6.5.669

Cited by 98 publications

(85 citation statements)

References 121 publications

(122 reference statements)

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“…Complex regional pain syndrome (CRPS) is a severe neuropathic pain condition characterized by persistent inflammation [12,19,30,54]. Our previous study demonstrated that circulating miRNAs in whole blood can be useful in stratification of patients with CRPS and that dysregulation of specific miRNAs correlates to symptoms and comorbidities associated with the disease [51].…”

Section: Introductionmentioning

confidence: 99%

Functional significance of macrophage-derived exosomes in inflammation and pain

McDonald

Tian

Qureshi

et al. 2014

Pain

270

206

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Exosomes, secreted microvesicles transporting microRNAs (miRNAs), mRNAs, and proteins through bodily fluids, facilitate intercellular communication and elicit immune responses. Exosomal contents vary depending on the source and the physiological conditions of cells and can provide insights into how cells and systems cope with physiological perturbations. Previous analysis of circulating miRNAs in patients with complex regional pain syndrome (CRPS), a debilitating chronic pain disorder, revealed a subset of miRNAs in whole blood that are altered in the disease. To determine functional consequences of alterations in exosomal biomolecules in inflammation and pain, we investigated exosome-mediated information transfer in vitro, in a rodent model of inflammatory pain and in exosomes from patients with CRPS. Mouse macrophage cells stimulated with lipopolysaccharides (LPS) secrete exosomes containing elevated levels of cytokines and miRNAs that mediate inflammation. Transcriptome sequencing of exosomal RNA revealed global alterations in both innate and adaptive immune pathways. Exosomes from LPS-stimulated cells were sufficient to cause NF-kappaB activation in naïve cells, indicating functionality in recipient cells. A single injection of exosomes attenuated thermal hyperalgesia in a mouse model of inflammatory pain, suggesting an immunoprotective role for macrophage-derived exosomes. We also show that circulating miRNAs altered in patients with complex regional pain syndrome are trafficked by exosomes. Macrophage-derived exosomes carry a protective signature that is altered when secreting cells are exposed to an inflammatory stimulus. With their systemic signaling capabilities, exosomes can induce pleiotropic effects potentially mediating the multifactorial pathology underlying chronic pain and should be explored for their therapeutic utility.

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Section: Introductionmentioning

confidence: 99%

Functional significance of macrophage-derived exosomes in inflammation and pain

McDonald

Tian

Qureshi

et al. 2014

Pain

270

206

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“…However, this does not indicate that these genes are not involved in the initiation or maintenance of such conditions. The primary predictor of postoperative pain is the existence of pre-operative pain and even minor tissue injuries can apparently facilitate later injuries leading to pain pathologies16, 17, 28, 50. It is known that initial injury to sensory neurons leads to a significantly enhanced growth response to subsequent injuries22, 29, 36.…”

Section: Discussionmentioning

confidence: 99%

Skin Incision Induces Expression of Axonal Regeneration-Related Genes in Adult Rat Spinal Sensory Neurons

Hill¹,

Harrison²,

Rau³

et al. 2010

The Journal of Pain

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Skin incision and nerve injury both induce painful conditions. Incisional and post-surgical pain is believed to arise primarily from inflammation of tissue and the subsequent sensitization of peripheral and central neurons. The role of axonal regeneration-related processes in development of pain has only been considered when there has been injury to the peripheral nerve itself, even though tissue damage likely induces injury of resident axons. We sought to determine if skin incision would affect expression of regeneration-related genes such as activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) neurons. ATF3 is absent from DRG neurons of the normal adult rodent, but is induced by injury of peripheral nerves and modulates the regenerative capacity of axons. Image analysis of immunolabeled DRG sections revealed that skin incision led to an increase in the number of DRG neurons expressing ATF3. RT-PCR indicated that other regeneration-associated genes (galanin, GAP-43, Gadd45a) were also increased, further suggesting an injury-like response in DRG neurons. Our finding that injury of skin can induce expression of neuronal injury/regeneration-associated genes may impact how clinical post-surgical pain is investigated and treated. Perspective Tissue injury, even without direct nerve injury, may induce a state of enhanced growth capacity in sensory neurons. Axonal regeneration-associated processes should be considered alongside nerve signal conduction and inflammatory/sensitization processes as possible mechanisms contributing to pain, particularly the transition from acute to chronic pain.

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“…The broad spectrum of symptoms includes pain, inflammation, sensory dysfunction, impaired motor function, and trophic disturbances [1-4]. CRPS is subdivided into CRPS-I (reflex sympathetic dystrophy) and CRPS-II (causalgia), based on the absence or presence of documented nerve injury respectively [5].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA modulation in complex regional pain syndrome

et al. 2011

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BackgroundAberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification.MethodsWe profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions.ResultsThree different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs.ConclusionsmiRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.

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Pathophysiology of complex regional pain syndrome

Cited by 98 publications

References 121 publications

Functional significance of macrophage-derived exosomes in inflammation and pain

Functional significance of macrophage-derived exosomes in inflammation and pain

Skin Incision Induces Expression of Axonal Regeneration-Related Genes in Adult Rat Spinal Sensory Neurons

MicroRNA modulation in complex regional pain syndrome

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