A new hypothesis for the pathophysiology of complex regional pain syndrome

Russo, Marc; Georgius, Peter; Santarelli, Danielle M.

doi:10.1016/j.mehy.2018.07.026

Cited by 31 publications

(19 citation statements)

References 176 publications

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“…Whilst CRPS was initially considered a neurological phenomenon, there is accumulating evidence that it is an immunoneurological disorder [7–9]. Early evidence for this can be found as far back as the 1950s in the response to oral corticosteroid administration in early presentations of the condition (< 6 months) [10].…”

Section: Introductionmentioning

confidence: 99%

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome

Russo¹,

Fiore

Vreden

et al. 2019

J Neuroinflammation

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BackgroundComplex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.MethodsWe characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis.ResultsWe have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation.ConclusionsThese findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.

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Section: Introductionmentioning

confidence: 99%

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome

Russo¹,

Fiore

Vreden

et al. 2019

J Neuroinflammation

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“…It is a chronic pain condition that lasts more than six months. Changes in the central and peripheral nervous systems are involved in the pathogenesis of this syndrome [9,10]. Symptoms may vary in degree, depending on the extent of tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Molecular Aspects of Regional Pain Syndrome

Baronio

Sadia

Paolacci

et al. 2020

Pain Research and Management

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The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoantibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients. As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory diseases. CRPS is more frequent in individuals of 61–70 years of age with a female to male ratio of 3 : 1. Menopause, migraine, osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.

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“…This is a cascade of events following an inflammatory response, resulting in an activation of glial cells especially including microglia and astrocytes located in the spinal cord and brain, which demonstrate a prominent role in nociception. 28 29 30 Upon activation, astrocytes proliferate, and increase expression of intermediate filaments such as GFAP. 4 31 32 33 In a vicious cycle, the activated astrocytes release inflammatory stimulants such as cytokines, neurotrophic factors.…”

Section: Discussionmentioning

confidence: 99%

Anti-Allodynic Effects of Polydeoxyribonucleotide in an Animal Model of Neuropathic Pain and Complex Regional Pain Syndrome

et al. 2020

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Background Spinal nerve ligation (SNL) model is one of the representative models of the neuropathic pain model. Neuropathic pain in a chronic post-ischemic pain (CPIP) mimics the symptoms of complex regional pain syndrome (CRPS). The administration of polydeoxyribonucleotide (PDRN), which has regenerative and anti-inflammatory effects, has been studied and is used in clinical practice treating various diseases. However, the analgesic effect of PDRN in a neuropathic pain or CRPS model remains unknown. Methods PDRN (3.3, 10, and 20 mg/kg) was administered into the subcutaneous (SC) layer of the hind paws of SNL and CPIP models. Mechanical anti-allodynic effects were then investigated using the von Frey test. In the immunohistochemical examination, dorsal root ganglia (DRG) and the spinal cord were harvested and examined for the expression of glial fibrillary acidic protein (GFAP) after the 20 mg PDRN injection. Results Mechanical allodynia was significantly alleviated by administration of PDRN in SNL and CPIP mice at all of the time point. As the dose of PDRN increased, the effect was greater. The 20 mg PDRN injection was found to have the most effective anti-allodynic effect. The increased expression of GFAP in DRG and the spinal cord of SNL and CPIP model decreased following the administration of PDRN than vehicle. Conclusion SC administration of PDRN results in the attenuation of allodynia and activation of astrocytes in neuropathic pain or CRPS models. We propose that PDRN can have significant potential advantages in neuropathic pain treatment.

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A new hypothesis for the pathophysiology of complex regional pain syndrome

Cited by 31 publications

References 176 publications

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome

Molecular Aspects of Regional Pain Syndrome

Anti-Allodynic Effects of Polydeoxyribonucleotide in an Animal Model of Neuropathic Pain and Complex Regional Pain Syndrome

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