scholarly journals Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Teruyuki Ishikura ◽  
Makoto Kinoshita ◽  
Mikito Shimizu ◽  
Yoshiaki Yasumizu ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Transcriptome Analysis ◽  
Mechanical Allodynia ◽  
Atp Release ◽  
Extracellular Atp ◽  
Hek293 Cells ◽  
Common Symptom ◽  
Pharmacological Inhibition ◽  
Atp Concentration ◽  
Aqp4 Antibody

Abstract Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. Methods We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. Results Development of mechanical allodynia was confirmed in rAQP4 IgG–treated rats. AQP4-Ab–mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG–treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG–treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. Conclusion Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.

scholarly journals ATP mediates neuropathic pain in neuromyelitis optica via microglial activation

2020 ◽  
Author(s):  
Teruyuki Ishikura ◽  
Makoto Kinoshita ◽  
Mikito Shimizu ◽  
Yoshiaki Yasumizu ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Neuromyelitis Optica ◽  
Transcriptome Analysis ◽  
Mechanical Allodynia ◽  
Microglial Activation ◽  
Atp Release ◽  
Common Symptom ◽  
Pain Model ◽  
Pharmacological Inhibition

Abstract Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. The aim of this study was to establish a novel animal model of NMOSD pain and to investigate its pathogenic mechanism. Methods We established an NMOSD pain model by injecting anti-AQP4 recombinant autoantibodies (AQP4-Ab) from NMOSD patient plasmablasts into rat spinal cords. We performed transcriptome analysis and pharmacological inhibition to elucidate the core mechanism of allodynia in the model. Results Development of mechanical allodynia was confirmed in the NMOSD pain model. AQP4-Ab mediated extracellular ATP release in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the NMOSD pain model. Furthermore, transcriptome analysis revealed microglial activation and elevated levels of IL-1β in NMOSD spinal cord. Inhibition of microglial activation and neutralization of IL-1β also attenuated neuropathic pain in the NMOSD rat model. In human patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. Conclusion A novel NMOSD pain model was established. ATP, microglial activation, and IL-1β secretion orchestrate the pathogenesis of NMOSD neuropathic pain.

scholarly journals Pannexin1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated free fatty acids in liver cells

2012 ◽  
Vol 303 (10) ◽  
pp. C1034-C1044 ◽  
Author(s):  
Feng Xiao ◽  
Shar L. Waldrop ◽  
Al-karim Khimji ◽  
Gordan Kilic
Keyword(s):  
Fatty Acids ◽  
Liver Injury ◽  
Free Fatty Acids ◽  
Atp Release ◽  
Liver Cells ◽  
Extracellular Atp ◽  
Pcr Analysis ◽  
Dependent Manner ◽  
Hepatic Inflammation ◽  
Atp Concentration

Hepatocyte lipoapoptosis induced by saturated free fatty acids (FFA) contributes to hepatic inflammation in lipotoxic liver injury, and the cellular mechanisms involved have not been defined. Recent studies have shown that apoptosis in nonhepatic cells stimulates ATP release via activation of pannexin1 (panx1), and extracellular ATP functions as a proinflammatory signal for recruitment and activation of the inflammatory cells. However, it is not known whether lipoapoptosis stimulates ATP release in liver cells. We found that lipoapoptosis induced by saturated FFA stimulated ATP release in liver cells that increased extracellular ATP concentration by more than fivefold above the values observed in healthy cells. This sustained pathophysiological ATP release was not dependent on caspase-3/7 activation. Inhibition of c-Jun NH2-terminal kinase (JNK), a key mediator of lipoapoptosis, with SP600125 blocked pathophysiological ATP release in a dose-dependent manner. RT-PCR analysis indicated that panx1 is expressed in hepatocytes and multiple liver cell lines. Notably, inhibition of panx1 expression with short hairpin (sh)RNA inhibited in part pathophysiological ATP release. Moreover, lipoapoptosis stimulated uptake of a membrane impermeable dye YoPro-1 (indicative of panx1 activation), which was inhibited by panx1 shRNA, probenecid, and mefloquine. These results suggest that panx1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated FFA. Thus panx1 may play an important role in hepatic inflammation by mediating an increase in extracellular ATP concentration in lipotoxic liver injury.

The Effect of Blocking of Antidromic Impulses by Capsaicin on Mechanical Allodynia in a Rat Model of Peripheral Neuropathic Pain

2004 ◽  
Vol 17 (1) ◽  
pp. 5 ◽  
Author(s):  
Jin Woo Shin ◽  
Kyung Don Hahm ◽  
Joong Woo Leem ◽  
Chul Hoo Park ◽  
Seung Woo Ku ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Peripheral Neuropathic Pain

scholarly journals The signaling role of extracellular ATP in co-culture of Shiraia sp. S9 and Pseudomonas fulva SB1 for enhancing hypocrellin A production

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xin Ping Li ◽  
Lu Lu Zhou ◽  
Yan Hua Guo ◽  
Jian Wen Wang
Keyword(s):  
Atp Release ◽  
Specific Inhibitor ◽  
Extracellular Atp ◽  
Oxidase Inhibitor ◽  
Disulfonic Acid ◽  
Early Event ◽  
Fungal Metabolites ◽  
Extracellular Signaling ◽  
Hypocrellin A

Abstract Background Adenosine 5′-triphosphate (ATP) plays both a central role as an intracellular energy source, and a crucial extracellular signaling role in diverse physiological processes of animals and plants. However, there are less reports concerning the signaling role of microbial extracellular ATP (eATP). Hypocrellins are effective anticancer photodynamic therapy (PDT) agents from bambusicolous Shiraia fungi. The co-culture of Shiraia sp. S9 and a bacterium Pseudomonas fulva SB1 isolated from Shiraia fruiting bodies was established for enhanced hypocrellin A (HA) production. The signaling roles of eATP to mediate hypocrellin biosynthesis were investigated in the co-culture. Results The co-culture induced release of eATP at 378 nM to the medium around 4 h. The eATP release was interdependent on cytosolic Ca2+ concentration and reactive oxygen species (ROS) production, respectively. The eATP production could be suppressed by the Ca2+ chelator EGTA or abolished by the channel blocker La3+, ROS scavenger vitamin C and NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). The bacterium-induced H2O2 production was strongly inhibited by reactive blue (RB), a specific inhibitor of membrane purinoceptors, but dependent on the induced Ca2+ influx in the co-culture. On the other hand, the application of exogenous ATP (exATP) at 10–300 µM to Shiraia cultures also promoted fungal conidiation and HA production, both of which were blocked effectively by the purinoceptor inhibitors pyridoxalphosphate-6-azophenyl-2′, 4′-disulfonic acid (PPADS) and RB, and ATP hydrolase apyrase. Both the induced expression of HA biosynthetic genes and HA accumulation were inhibited significantly under the blocking of the eATP or Ca2+ signaling, and the scavenge of ROS in the co-culture. Conclusions Our results indicate that eATP release is an early event during the intimate bacterial–fungal interaction and eATP plays a signaling role in the bacterial elicitation on fungal metabolites. Ca2+ and ROS are closely linked for activation of the induced ATP release and its signal transduction. This is the first report on eATP production in the fungal–bacterial co-culture and its involvement in the induced biosynthesis of fungal metabolites. Graphic abstract

scholarly journals Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments

2020 ◽  
Vol 20 (4) ◽  
pp. 683-691
Author(s):  
Laura Mustonen ◽  
Tommi Aho ◽  
Hanna Harno ◽  
Eija Kalso
Keyword(s):  
Breast Cancer ◽  
Neuropathic Pain ◽  
Psychological Factors ◽  
Mechanical Allodynia ◽  
Cold Pressor Test ◽  
Pain Tolerance ◽  
Cancer Surgery ◽  
Breast Cancer Surgery ◽  
Cold Pain ◽  
Static Mechanical

AbstractObjectivesStatic mechanical allodynia (SMA), i. e., pain caused by normally non-painful static pressure, is a prevalent manifestation of neuropathic pain (NP). Although SMA may significantly affect the patient’s daily life, it is less well studied in the clinical context. We aimed to characterize SMA in women with chronic post-surgical NP (CPSNP) after breast cancer surgery. Our objective was to improve understanding of the clinical picture of this prevalent pain condition. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery (Mustonen et al. Pain. 2019;160:246–56).MethodsWe studied SMA in 132 patients with CPSNP after breast cancer surgery. The presence, location, and intensity of SMA were assessed at clinical sensory examination. The patients gave self-reports of pain with the Brief Pain Inventory (BPI). We studied the association of SMA to type of surgery, oncological treatments, BMI, other pains, and psychological factors. General pain sensitivity was assessed by the cold pressor test.ResultsSMA was prevalent (84%) in this cohort whereas other forms of allodynia were scarce (6%). Moderate-to-severe SMA was frequently observed even in patients who reported mild pain in BPI. Breast and the side of chest were the most common locations of SMA. SMA was associated with breast surgery type, but not with psychological factors. Severe SMA, but not self-reported pain, was associated with lower cold pain tolerance.ConclusionsSMA is prevalent in post-surgical NP after breast cancer surgery and it may represent a distinct NP phenotype. High intensities of SMA may signal the presence of central sensitization.ImplicationsSMA should be considered when examining and treating patients with post-surgical NP after breast cancer surgery.

scholarly journals Tongluo Zhitong Prescription Alleviates Allodynia, Hyperalgesia, and Dyskinesia in the Chronic Constriction Injury Model of Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Zhiyong Wang ◽  
Jianwei Wang ◽  
Lihua Qin ◽  
Weiguang Zhang
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Catgut Suture ◽  
Cold Allodynia ◽  
Injury Model ◽  
Neuropathic Pain Model ◽  
Gait Function ◽  
Chronic Constriction Injury Model ◽  
Heat Hyperalgesia

Neuropathic pain is common in clinical practice. Exploration of new drug therapeutics has always been carried out for more satisfactory effects and fewer side-effects. In the present study, we aimed to investigate effects of Tongluo Zhitong Prescription (TZP), a compounded Chinese medicine description, on neuropathic pain model of rats with chronic constriction injury (CCI). The CCI model was established by loosely ligating sciatic nerve with catgut suture, proximal to its trifurcation. The static and dynamic allodynia, heat hyperalgesia, mechanical allodynia, cold allodynia, and gait were assessed. Our results showed that TZP alleviated CCI-induced static and dynamic allodynia, suppressed heat hyperalgesia and cold and mechanical allodynia, and improved gait function. These results suggest that TZP could alleviate neuropathic pain. Further experiments are needed to explore its mechanisms.

scholarly journals Dynamic regulation of extracellular ATP in Escherichia coli

2017 ◽  
Vol 474 (8) ◽  
pp. 1395-1416 ◽  
Author(s):  
Cora Lilia Alvarez ◽  
Gerardo Corradi ◽  
Natalia Lauri ◽  
Irene Marginedas-Freixa ◽  
María Florencia Leal Denis ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Atpase Activity ◽  
Atp Release ◽  
Membrane Vesicles ◽  
Fold Increase ◽  
Extracellular Atp ◽  
Outer Membrane Vesicles ◽  
Dynamic Regulation ◽  
E Coli

We studied the kinetics of extracellular ATP (ATPe) in Escherichia coli and their outer membrane vesicles (OMVs) stimulated with amphipatic peptides melittin (MEL) and mastoparan 7 (MST7). Real-time luminometry was used to measure ATPe kinetics, ATP release, and ATPase activity. The latter was also determined by following [32P]Pi released from [γ-32P]ATP. E. coli was studied alone, co-incubated with Caco-2 cells, or in rat jejunum segments. In E. coli, the addition of [γ-32P]ATP led to the uptake and subsequent hydrolysis of ATPe. Exposure to peptides caused an acute 3-fold (MST7) and 7-fold (MEL) increase in [ATPe]. In OMVs, ATPase activity increased linearly with [ATPe] (0.1–1 µM). Exposure to MST7 and MEL enhanced ATP release by 3–7 fold, with similar kinetics to that of bacteria. In Caco-2 cells, the addition of ATP to the apical domain led to a steep [ATPe] increase to a maximum, with subsequent ATPase activity. The addition of bacterial suspensions led to a 6–7 fold increase in [ATPe], followed by an acute decrease. In perfused jejunum segments, exposure to E. coli increased luminal ATP 2 fold. ATPe regulation of E. coli depends on the balance between ATPase activity and ATP release. This balance can be altered by OMVs, which display their own capacity to regulate ATPe. E. coli can activate ATP release from Caco-2 cells and intestinal segments, a response which in vivo might lead to intestinal release of ATP from the gut lumen.

scholarly journals Plasticity-Related PKMζSignaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jeongsoo Han ◽  
Minjee Kwon ◽  
Myeounghoon Cha ◽  
Motomasa Tanioka ◽  
Seong-Karp Hong ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Neural Plasticity ◽  
Mechanical Allodynia ◽  
Insular Cortex ◽  
Long Term Potentiation ◽  
Inhibitory Peptide ◽  
Term Potentiation ◽  
Potential Applications

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ(PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζin the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. Afterζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ(p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζwere decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζand that ZIP has potential applications for relieving chronic pain.

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