Neuroinflammation, Neuroautoimmunity, and the Co-Morbidities of Complex Regional Pain Syndrome

Cooper, Mark S.; Clark, Vincent P.

doi:10.1007/s11481-012-9392-x

Cited by 37 publications

(32 citation statements)

References 161 publications

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“…Although the mechanisms are unclear, chronic, nonresolving inflammation in CRPS is characterized by prolonged secretion of proinflammatory factors, disruption of the blood–brain barrier, and development of autoimmunity [17]. The pain and inflammation in CRPS are not alleviated by commonly used analgesics or anti-inflammatory drugs, and the development of persistent pain states and the maintenance of chronic inflammation point to systemic aberrations.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…The agents entering the OB may spread further in the brain to cause neurological disorders. It is suggested that inflammatory responses can spread in the CNS both anterogradely or retrogradely via axonal projections (81). For instance, corneal inflammation induced by instillation of benzalkonium chloride damages primary sensory neurons in the trigeminal ganglion, leading to the activation of second-order neurons and glial cells in the brain stem and to the production of pro-inflammatory cytokines (82).…”

Section: Discussionmentioning

confidence: 99%

Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa

Imamura

Hasegawa-Ishii

2016

Front. Immunol.

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Olfactory sensory neurons (OSNs) are the receptor cells for the sense of smell. Although cell bodies are located in the olfactory mucosa (OM) of the nasal cavity, OSN axons directly project to the olfactory bulb (OB) that is a component of the central nervous system (CNS). Because of this direct and short connection from this peripheral tissue to the CNS, the olfactory system has attracted attention as a port-of-entry for environmental toxicants that may cause neurological dysfunction. Selected viruses can enter the OB via the OM and directly affect the CNS. On the other hand, environmental toxicants may induce inflammatory responses in the OM, including infiltration of immune cells and production of inflammatory cytokines. In addition, these inflammatory responses cause the loss of OSNs that are then replaced with newly generated OSNs that re-connect to the OB after inflammation has subsided. It is now known that immune cells and cytokines in the OM play important roles in both degeneration and regeneration of OSNs. Thus, the olfactory system is a unique neuroimmune interface where interaction between nervous and immune systems in the periphery significantly affects the structure, neuronal circuitry, and immunological status of the CNS. The mechanisms by which immune cells regulate OSN loss and the generation of new OSNs are, however, largely unknown. To help develop a better understanding of the mechanisms involved, we have provided a review of key research that has investigated how the immune response in the OM affects the pathophysiology of OSNs.

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“…Hence, one important methodological aspect of the current study is that we directly injected corticosteroids into the thoracic sympathetic ganglion. Autoimmune attack against peripheral nerves might trigger leukocyte extravasation, autoantibody exudation, neuroinflammation, and neuroimmune activation in associated dorsal root ganglia, sympathetic ganglion, and the spinal cord, and this has been suggested as a possible underlying mechanism of the development of CRPS [5,13,23,30,34,54]. There are data supporting pain improvement in CRPS patients after the use of systemic steroids [11,19,28].…”

Section: Discussionmentioning

confidence: 99%

Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: A double-blind randomized controlled study

Rocha

Teixeira

Yeng

et al. 2014

Pain

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Pain relief in complex regional pain syndrome (CRPS) remains a major challenge, in part due to the lack of evidence-based treatment trials specific for this condition. We performed a long-term randomized, double-blinded active-control study to evaluate the efficacy of thoracic sympathetic block (TSB) for upper limb type I CRPS. The study objective was to evaluate the analgesic effect of TSB in CRPS. Patients with CRPS type I were treated with standardized pharmacological and physical therapy and were randomized to either TSB or control procedure as an add-on treatment. Clinical data, pain intensity, and interference (Brief Pain Inventory), pain dimensions (McGill Pain Questionnaire [MPQ]), neuropathic characteristics (Neuropathic Pain Symptom Inventory [NPSI]), mood, upper limb function (Disabilities of Arm, Shoulder and Hand), and quality of life were assessed before, and at 1 month and 12 months after the procedure. Thirty-six patients (19 female, 44.7 ± 11.1 years of age) underwent the procedure (17 in the TSB group). Average pain intensity at 1 month was not significantly different after TSB (3.5 ± 3.2) compared to control procedure (4.8 ± 2.7; P=0.249). At 12 months, however, the average pain item was significantly lower in the TSB group (3.47 ± 3.5) compared to the control group (5.86 ± 2.9; P=0.046). Scores from the MPQ, evoked-pain symptoms subscores (NPSI), and depression scores (Hospital Anxiety and Depression Scale) were significantly lower in the TSB group compared to the control group at 1 and at 12 months. Other measurements were not influenced by the treatment. Quality of life was only slightly improved by TSB. No major adverse events occurred. Larger, multicentric trials should be performed to confirm these original findings.

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Neuroinflammation, Neuroautoimmunity, and the Co-Morbidities of Complex Regional Pain Syndrome

Cited by 37 publications

References 161 publications

Functional significance of macrophage-derived exosomes in inflammation and pain

Functional significance of macrophage-derived exosomes in inflammation and pain

Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa

Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: A double-blind randomized controlled study

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