Neurobiological Mechanisms of Pain in Sickle Cell Disease

Abstract Pain is a frequent complaint of people living with sickle cell disease (SCD); however, the neurobiology of pain in SCD remains poorly understood. Whereas this pain has been thought to be primarily related to visceral and somatic tissue injury subsequent to vaso-occlusion events, emerging evidence from human and animal studies has suggested that a component of SCD pain may be related to neuropathic processes. Significant knowledge has been obtained from studies of molecular and neurobiological mechanisms leading to and maintaining neuropathic pain. Some of the most promising evidence has implicated major roles of protein kinase C and Ca2+/calmodulin-dependent protein kinase II, and their interaction with the N-methyl-D-aspartate receptors and the transient receptor potential vanilloid 1 receptor in the development of neuropathic pain. The latest evidence from our studies suggests that these pathways are important for SCD pain as well. Coupled with emerging animal models of SCD pain, we can now start to elucidate neurobiological mechanisms underlying pain in SCD, which may lead to better understanding and effective therapies.

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Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease

Blood ◽

10.1182/blood-2010-12-327429 ◽

2011 ◽

Vol 118 (12) ◽

pp. 3376-3383 ◽

Cited By ~ 96

Author(s):

Cheryl A. Hillery ◽

Patrick C. Kerstein ◽

Daniel Vilceanu ◽

Marie E. Barabas ◽

Dawn Retherford ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Emergency Department Visits ◽

Transient Receptor Potential Vanilloid ◽

Cell Disease ◽

Primary Afferent ◽

Mechanical Hypersensitivity ◽

Transient Receptor

Abstract Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.

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Neuronal transient receptor potential (TRP) channels and noxious sensory detection in sickle cell disease

Neuroscience Letters ◽

10.1016/j.neulet.2018.11.056 ◽

2019 ◽

Vol 694 ◽

pp. 184-191 ◽

Cited By ~ 7

Author(s):

Katelyn E. Sadler ◽

Cheryl L. Stucky

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Cell Disease ◽

Transient Receptor

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Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease

Pharmacogenomics ◽

10.2217/pgs-2017-0198 ◽

2018 ◽

Vol 19 (5) ◽

pp. 401-411 ◽

Cited By ~ 11

Author(s):

Ellie H Jhun ◽

Xiaoyu Hu ◽

Nilanjana Sadhu ◽

Yingwei Yao ◽

Ying He ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Cell Disease ◽

Transient Receptor

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Health-related quality of life and neuropathic pain in sickle cell disease in Jamaica

Disability and Health Journal ◽

10.1016/j.dhjo.2021.101107 ◽

2021 ◽

pp. 101107

Author(s):

Rachel Bartlett ◽

Zachary Ramsay ◽

Amza Ali ◽

Justin Grant ◽

Angela Rankine-Mullings ◽

...

Keyword(s):

Quality Of Life ◽

Neuropathic Pain ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Health Related Quality ◽

Cell Disease ◽

Related Quality ◽

Health Related

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Neuropathic Pain in Children with Sickle Cell Disease: The Hidden Side of the Vaso-Occlusive Crisis

Children ◽

10.3390/children8020084 ◽

2021 ◽

Vol 8 (2) ◽

pp. 84

Author(s):

Jeanne Sigalla ◽

Nathalie Duparc Alegria ◽

Enora Le Roux ◽

Artemis Toumazi ◽

Anne-Françoise Thiollier ◽

...

Keyword(s):

Risk Factors ◽

Neuropathic Pain ◽

Sickle Cell Disease ◽

Sex Ratio ◽

Prospective Study ◽

Sickle Cell ◽

Clinical Presentation ◽

Early Stage ◽

Cell Disease ◽

A Prospective Study

The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients (n = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient’s age, sex, and clinical presentation.

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The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽

10.1371/journal.pone.0255956 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0255956

Author(s):

Hassan Brim ◽

James Taylor ◽

Muneer Abbas ◽

Kimberly Vilmenay ◽

Mohammad Daremipouran ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Gut Microbiome ◽

Tissue Injury ◽

Organ Damage ◽

Composition Analysis ◽

Cell Disease ◽

Blood Disorder ◽

Major Player ◽

Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

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Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

10.21248/gups.60883 ◽

2021 ◽

Author(s):

◽

Tabea Osthues

Keyword(s):

Neuropathic Pain ◽

Signaling Pathways ◽

Nerve Injury ◽

Inflammatory Mediators ◽

Pain Perception ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Wild Type ◽

Injured Nerve

Neuropathic pain, a form of chronic pain, is a steadily rising health problem due to health costs and increasing numbers of patients. Neuropathic pain conditions arise upon metabolic disorders, infections, chemotherapeutic treatment, trauma or nerve injury. Especially nerve injury induced neuropathic pain is characterized by spontaneous or ongoing pain due to neuroimmune interactions. Thereby, inflammatory mediators, released by the injured nerve, recruit to and activate immune cells at the site of injury. Those mediators further activate transient receptor potential vanilloid 1 (TRPV1), a known channel involved in pain perception, or bind to G-protein coupled receptors (GPCR) in peripheral nerve endings. The following activated second messenger signaling pathways lead to sensitization of TRPV1. One of those GPCRs is G2A. The overall aim of this thesis was to investigate the role of G2A in nerve-injury induced neuropathic pain. For this, the common mouse model of nerve-injury induced neuropathic pain, the spared-nerve injury, was used. As measurements with dynamic plantar aesthesiometer showed, G2A-deficiency leads to reduced mechanical hypersensitivity. Upon analysis with FACS, ELISA and Luminex a reduced number of macrophages and neutrophils at the injured nerve, as well as less inflammatory mediators (TNFα, IL-6, VEGF) in G2A-deficient animals was observed. In dorsal root ganglia (DRGs) there was only a reduced number of macrophages and less IL-12 observed in G2A-deficient animals. Additionally, in wild-type mice, G2A agonist 9-HODE was elevated at the injured nerve, as a LC-MS/MS analysis showed. To investigate the underlying pathways of G2A-9-HODE signaling, a proteom screen was performed. This screen revealed upregulation of multiple proteins involved in migration in wild-type macrophages. Additionally, Ca-Imaging and transwell migration assays showed that the G2A antagonist G2A11, had desensitizing effects on DRG neurons and inhibited macrophage migration. Overall, the results suggest that loss of G2A has dual effects. On the one hand loss of G2A is antinociceptive. On the other hand, G2A-deficiency leads to reduced inflammation, suggesting G2A as promising target in treatment of neuropathic pain. Here, an antagonist had inhibitory effects on the migration and the sensitization.

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