scholarly journals Senso-Immunologic Prospects for Complex Regional Pain Syndrome Treatment

2022 ◽  
Vol 12 ◽  
Author(s):  
Takayuki Okumo ◽  
Yasunori Takayama ◽  
Kenta Maruyama ◽  
Mami Kato ◽  
Masataka Sunagawa
Keyword(s):  
Complex Regional Pain Syndrome ◽  
Transient Receptor Potential ◽  
Pain Treatment ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Pain Syndrome ◽  
Receptor Potential ◽  
Painful Condition ◽  
Paradoxical Situation ◽  
Bone Atrophy

Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption via enhanced osteoclast differentiation and activation. Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.

scholarly journals The Role of Ca2+-NFATc1 Signaling and Its Modulation on Osteoclastogenesis

2020 ◽  
Vol 21 (10) ◽  
pp. 3646
Author(s):  
Jung Yun Kang ◽  
Namju Kang ◽  
Yu-Mi Yang ◽  
Jeong Hee Hong ◽  
Dong Min Shin
Keyword(s):  
Bone Loss ◽  
Calcium Signaling ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Osteoclast Differentiation ◽  
Receptor Potential ◽  
Cytosolic Calcium ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Transient Receptor

The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption. Cytosolic calcium binds to calmodulin and subsequently activates calcineurin, leading to NFATc1 activation, a master transcription factor required for osteoclast differentiation. Targeting the various activation processes in osteoclastogenesis provides various therapeutic strategies for bone loss. Diverse compounds that modulate calcium signaling have been applied to regulate osteoclast differentiation and, subsequently, attenuate bone loss. Thus, in this review, we summarized the modulation of the NFATc1 pathway through various compounds that regulate calcium signaling and the calcium influx machinery. Furthermore, we addressed the involvement of transient receptor potential channels in osteoclastogenesis.

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

2019 ◽  
Vol 9 (8) ◽  
pp. 197 ◽  
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.

scholarly journals Gain-of-Function Mutations in the Transient Receptor Potential Channels TRPV1 and TRPA1: How Painful?

2014 ◽  
pp. S205-S213 ◽  
Author(s):  
S. BOUKALOVA ◽  
F. TOUSKA ◽  
L. MARSAKOVA ◽  
A. HYNKOVA ◽  
L. SURA ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Pain Syndrome ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Single Amino Acid ◽  
Voltage Sensitivity ◽  
Gain Of Function ◽  
Potential Channels ◽  
Transient Receptor

Gain-of-function (GOF) mutations in ion channels are rare events, which lead to increased agonist sensitivity or altered gating properties, and may render the channel constitutively active. Uncovering and following characterization of such mutants contribute substantially to the understanding of the molecular basis of ion channel functioning. Here we give an overview of some GOF mutants in polymodal ion channels specifically involved in transduction of painful stimuli – TRPV1 and TRPA1, which are scrutinized by scientists due to their important role in development of some pathological pain states. Remarkably, a substitution of single amino acid in the S4-S5 region of TRPA1 (N855S) has been recently associated with familial episodic pain syndrome. This mutation increases chemical sensitivity of TRPA1, but leaves the voltage sensitivity unchanged. On the other hand, mutations in the analogous region of TRPV1 (R557K and G563S) severely affect all aspects of channel activation and lead to spontaneous activity. Comparison of the effects induced by mutations in homologous positions in different TRP receptors (or more generally in other distantly related ion channels) may elucidate the gating mechanisms conserved during evolution.

scholarly journals Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption

2020 ◽  
Vol 22 (1) ◽  
pp. 180
Author(s):  
Hiroyuki Okada ◽  
Koji Okabe ◽  
Sakae Tanaka
Keyword(s):  
Endoplasmic Reticulum ◽  
Bone Resorption ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Osteoclast Differentiation ◽  
Receptor Potential ◽  
Calcium Oscillations ◽  
Fine Tuning ◽  
Transient Receptor ◽  
And Function

Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.

scholarly journals Brain Neuroplastic Changes Accompany Anxiety and Memory Deficits in a Model of Complex Regional Pain Syndrome

2014 ◽  
Vol 121 (4) ◽  
pp. 852-865 ◽  
Author(s):  
Maral Tajerian ◽  
David Leu ◽  
Yani Zou ◽  
Peyman Sahbaie ◽  
Wenwu Li ◽  
...  
Keyword(s):  
Working Memory ◽  
Mouse Model ◽  
Complex Regional Pain Syndrome ◽  
Structural Changes ◽  
Brain Plasticity ◽  
Pain Syndrome ◽  
The United States ◽  
Cast Immobilization ◽  
Cognitive Changes ◽  
Painful Condition

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.

scholarly journals Transient Receptor Potential Melastatin 8 Contributes to Cystitis-Induced Neuronal Sprouting and Pain Hypersensitivity Through AKT/Mtor Signaling Pathway in Interstitial Cystitis/ Bladder Pain Syndrome

2021 ◽  
Author(s):  
Liyang Wu ◽  
Fei Zhou ◽  
Jianzhong Zhang ◽  
Ran Chang ◽  
Fei Wang ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Transient Receptor Potential ◽  
Pain Syndrome ◽  
Receptor Potential ◽  
Bladder Pain Syndrome ◽  
Control Group ◽  
Mtor Signaling Pathway ◽  
Bladder Pain ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Abstract Transient receptor potential melastatin 8 (TRPM8) is associated with the pathophysiology of interstitial cystitis (IC)/ bladder pain syndrome (BPS). We investigated the mechanism of TRPM8 in neuroproliferation and pain, as well as the relevance of the Akt/mTOR signaling pathway in mice with IC/BPS. The model of IC/BPS was established in wild and TRPM8-/- mice. The mechanical sensitivity was measured. The number of neurite segments, length of neurites, and density of neurites were all counted. IL-6 and norepinephrine levels were detected by ELISA, Western blot was used to detect protein levels of TRPM8, Akt, p-Akt, mTOR, p-mTOR. Immunofluorescence was used to detect TRPM8 expression and distribution in neurites, neurons, and sensory nerves in mouse bladder tissue. Pain threshold in the IC / BPS group was decreased, and neurite segments, length, and density were all significantly enhanced when compared to the control group. The parameters in the TRPM8 agonists(menthol)+IC/BPS group were more statistically significant. Neurite number and density were lower in TRPM8-/-+IC/BPS mice than in IC/BPS mice. The expression of TRPM8 and the ratios of p-Akt/Akt and p-mTOR/mTOR rose in the IC/BPS group. In TRPM8-/-+IC/BPS mice, the ratios of p-Akt/Akt and p-mTOR/mTOR were not substantially different from those in the control group. TRPM8-/-+IC/BPS mice had considerably lower levels of serum IL-6 and urine norepinephrine than wild-type IC/BPS mice. TRPM8 can induce pain hypersensitivity and sensory nerve proliferation by activating Akt/mTOR pathway and raising the expression of IL-6 and norepinephrine in IC/BPS models. These findings offer new perspectives on IC/BPS treatment.

scholarly journals Somatic and Abdominal Acupuncture for Pain Treatment in Adolescent Complex Regional Pain Syndrome (CRPS) of the Upper Limb: A Case Report

Children ◽  
2021 ◽  
Vol 8 (12) ◽  
pp. 1187
Author(s):  
Giuliano Marchetti ◽  
Alessandro Vittori ◽  
Ilaria Mascilini ◽  
Elisa Francia ◽  
Antonella Insalaco ◽  
...  
Keyword(s):  
Complex Regional Pain Syndrome ◽  
Upper Limb ◽  
Conservative Therapy ◽  
Pain Treatment ◽  
Pain Syndrome ◽  
Initial Stimulus ◽  
Left Wrist ◽  
Abdominal Acupuncture ◽  
Potential Alternative ◽  
Pediatric Populations

Complex regional pain syndrome (CRPS) is still poorly understood. It is a pain disorder in which pain is disproportionate to the initial stimulus. There is no specific therapy for CRPS, but it can be managed by a combination of treatments. We report a 13-year-old girl with CRPS of the upper limb treated with somatic and abdominal acupuncture. She described a severe, pulsating pain in the left wrist and hand, with hypersensitivity, allodynia, a marked reduction in strength, and swelling and sweating at the level of the fingers. Pain began three months previously, after a trauma to the left wrist. The diagnostic tests performed were negative. At the first visit we recommended oral tramadol. During the first two sessions we used somatic acupuncture. At the third session, the girl reported suffering intolerable pain in the affected limb during the previous sessions, so we decided to use abdominal acupuncture. After 8 sessions of abdominal acupuncture the pain completely disappeared. Acupuncture could be a potential alternative when conservative therapy with physical and medical treatment fails, but more often parents and adolescents prefer this therapy since other comorbidities are often present in pediatric populations and abdominal acupuncture could be a valuable alternative aid.

scholarly journals Review of complex regional pain syndrome and the role of the neuroimmune axis

2021 ◽  
Vol 17 ◽  
pp. 174480692110066
Author(s):  
Amrita Prasad, MD ◽  
Krishnan Chakravarthy, MD
Keyword(s):  
Complex Regional Pain Syndrome ◽  
Clinical Studies ◽  
Pain Treatment ◽  
Relevant Literature ◽  
Pain Syndrome ◽  
Immunomodulatory Effects ◽  
Pain Mechanisms ◽  
Preclinical And Clinical Studies ◽  
Neuroimmune Axis

Background Complex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS. Study design A narrative review of preclinical and clinical studies provided an overview of the pain and inflammatory mechanisms in CRPS and addressed the effect of neurostimulation on immunomodulation. Methods A systematic literature search was conducted based on the PRISMA guidelines between September 2015 to September 2020. Data sources included relevant literature identified through searches of PubMed, Embase and the Cochrane Database of Systematic Reviews. Results Sixteen preclinical and eight clinical studies were reviewed. Preclinical studies identified different mechanisms of pain development in the acute and chronic CRPS phases. Several preclinical and clinical studies investigating inflammatory mechanisms, autoimmunity, and genetic profiles in CRPS, supported a role of neuroinflammation in the pathophysiology of CRPS. The immunomodulatory effects of neurostimulation therapy is still unclear, despite clinical improvement in the CRPS patients. Conclusions Increasing evidence supports a role for inflammation and neuroinflammation in CRPS pathophysiology. Preliminary neurostimulation findings, together with the role of (neuro)inflammation in CRPS, seems to provide a compelling rationale for its use in CRPS pain treatment. The possible immunomodulatory effects of neurostimulation opens new therapeutic possibilities, however further research is needed to gain a better understanding of the working mechanisms.

scholarly journals A Proposed Molecular Mechanism for Physical Analgesia in Chronic Pain

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Norio Saito ◽  
Rei Shima ◽  
Yurika Yamada ◽  
Masaru Nagaoka ◽  
Etsuro Ito ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Pain Relief ◽  
Molecular Mechanism ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Pain Treatment ◽  
Receptor Potential ◽  
Alternative Methods ◽  
Heavy Burden ◽  
Transient Receptor

Although pain is indispensable for survival, chronic pain places a heavy burden on humans. As the efficacy of opioid treatment is limited, the development of alternative methods of pain relief without medication is desirable. Recently, we have developed a novel method of physical analgesia using an adhesive “pyramidal thorn patch.” When we apply about 3 trials of these patches on the skin of a pain region, the pain region moves toward the spinal cord like a “cutaneous rabbit,” and finally, the pain vanishes. In the present review, we propose a molecular mechanism for this analgesic method or pain relief following application of the pyramidal thorn patch where firstly the mechanoreceptors and their related nerves under the skin are activated in response to touch. Transient receptor potential (TRP) channels serve as mechanosensitive channels within these mechanoreceptors. We further propose that activation of the nerves connected with the mechanoreceptors releases oxytocin, which has an antinociceptive function and activates TRP channels to hyperpolarize the pain signal nerves. We believe that our system will pave the way for alternative pain treatment.

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