Kinin B1 receptor is involved in mechanical nociception in a fibromyalgia-like model in mice

Fibromyalgia-like models in mice induced by reserpine have opened a new avenue to understanding the molecular mechanisms behind this complex and incapacitating pain syndrome. The kinin B1 receptor (B1R) contributes to mechanical allodynia and acute coping behavior in mice with inflammatory and immunological disorders. This study has replicated previous data where amine depletion induced by reserpine significantly decreased the dopamine and serotonin levels in the prefrontal cortex (PFC), hippocampus (HPC), and spinal cord of mice. The animals subjected to the reserpine fibromyalgia model also showed decreased paw withdrawal threshold (PWT) and increased the immobility time in the forced swimming test (FST). Genetic ablation of B1R or pharmacological blockade by selective kinin B1R antagonist R-715 (acute i.p. treatment) counteracted the mechanical allodynia and increased immobility time induced by reserpine. However, neither pharmacological nor genetic inhibition of B1R reversed monoamine depletion. Our data confirm that reserpine induced a fibromyalgia-like phenotype in mice and reiterated the role of B1R on acute coping behavior and nociception modulation.

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NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

10.21203/rs.3.rs-35729/v1 ◽

2020 ◽

Author(s):

Meng Liu ◽

Su-Bo Zhang ◽

Yu-Xuan Luo ◽

Yan-Ling Yang ◽

Xiang-Zhong Zhang ◽

...

Keyword(s):

Binding Site ◽

Dorsal Horn ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Molecular Mechanisms ◽

Target Genes ◽

Painful Neuropathy ◽

Withdrawal Threshold ◽

Spinal Dorsal ◽

Paclitaxel Treatment

Abstract Background: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, microarray analysis were performed to explore the molecular mechanism. Results: We found that paclitaxel treatment increased the expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TSS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy directly upregulated the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

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Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation

Mediators of Inflammation ◽

10.1155/2021/1791222 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Jialiang Chen ◽

Honglu Ding ◽

Bolong Liu ◽

Xiangfu Zhou ◽

Xin Zhou ◽

...

Keyword(s):

Interstitial Cystitis ◽

Mechanical Allodynia ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Microglia Activation ◽

Bladder Pain ◽

Withdrawal Threshold ◽

Notch1 Signaling ◽

Tnf Α ◽

The Impact

Aims. Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. Methods. CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1β in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. Results. Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1β. Conclusion. Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.

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Blockade of the kinin B1 receptor counteracts the depressive-like behaviour and mechanical allodynia in ovariectomised mice

Behavioural Brain Research ◽

10.1016/j.bbr.2021.113439 ◽

2021 ◽

pp. 113439

Author(s):

Izaque de Souza Maciel ◽

Vanessa Machado Azevedo ◽

Patricia Oliboni ◽

Maria Martha Campos

Keyword(s):

Mechanical Allodynia ◽

B1 Receptor ◽

Kinin B1 Receptor

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NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

Journal of Neuroinflammation ◽

10.1186/s12974-020-01992-1 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Meng Liu ◽

Su-Bo Zhang ◽

Yu-Xuan Luo ◽

Yan-Ling Yang ◽

Xiang-Zhong Zhang ◽

...

Keyword(s):

Binding Site ◽

Dorsal Horn ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Molecular Mechanisms ◽

Target Genes ◽

Painful Neuropathy ◽

Withdrawal Threshold ◽

Spinal Dorsal ◽

Paclitaxel Treatment

Abstract Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. Results We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

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Blockade of Kinin B1 receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice

10.1101/2020.09.01.278416 ◽

2020 ◽

Author(s):

Izaque de Souza Maciel ◽

Vanessa Machado Azevedo ◽

Patricia Oliboni ◽

Maria Martha Campos

Keyword(s):

Mechanical Allodynia ◽

Tail Suspension Test ◽

Selective Inhibition ◽

Depression Symptoms ◽

Ovariectomized Mice ◽

Estrogen Production ◽

Immobility Time ◽

Somatosensory Stimulus ◽

Kinin B1 Receptor ◽

Genetic Deletion

AbstractMenopause is related to a decline in ovarian estrogen production, affecting the perception of the somatosensory stimulus, changing the immune-inflammatory systems, and triggering depressive symptoms. Inhibition of kinin B1 and B2 receptors (B1R and B2R) inhibits the depressive-like behavior and mechanical allodynia induced by immune-inflammatory mediators in mice. However, there is no evidence on the role of kinin receptors in depressive-like and nociceptive behavior in female mice submitted to bilateral ovariectomy. This study shows that ovariectomized mice (OVX) developed time-related mechanical allodynia and increased immobility time in the tail suspension test (TST). The genetic deletion of B1R, or the pharmacological blockade by selective kinin B1R antagonist R-715 (acute, i.p), reduced the increase of immobility time and mechanical allodynia induced by ovariectomy. Neither genetic deletion nor pharmacological inhibition of B2R (HOE 140, i.p) prevented the behavioral changes elicited by OVX. Our data suggested a particular modulation of kinin B1R in the nociceptive and depressive-like behavior in ovariectomized mice. Selective inhibition of the B1R receptor may be a new pharmacological target for treating pain and depression symptoms in women on the perimenopause/menopause period.

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Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms22010145 ◽

2020 ◽

Vol 22 (1) ◽

pp. 145

Author(s):

Rohan Umesh Parekh ◽

Srinivas Sriramula

Keyword(s):

Protein Expression ◽

Renin Angiotensin System ◽

Neuronal Cultures ◽

Wild Type ◽

High Concentration ◽

Neurogenic Hypertension ◽

B1 Receptor ◽

Gene And Protein Expression ◽

Kinin B1 Receptor ◽

Specific Antagonist

Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.

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Up-regulation of kinin B1 receptor in the lung of streptozotocin-diabetic rat: autoradiographic and functional evidence

British Journal of Pharmacology ◽

10.1038/sj.bjp.0704999 ◽

2003 ◽

Vol 138 (1) ◽

pp. 13-22 ◽

Cited By ~ 26

Author(s):

Rose Mari J Vianna ◽

Brice Ongali ◽

Domenico Regoli ◽

João Batista Calixto ◽

Réjean Couture

Keyword(s):

Diabetic Rat ◽

B1 Receptor ◽

Kinin B1 Receptor ◽

Streptozotocin Diabetic Rat

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Agonist Activity at the Kinin B1 Receptor: Structural Requirements of the Central Tetrapeptide

Journal of Medicinal Chemistry ◽

10.1021/jm000319u ◽

2001 ◽

Vol 44 (2) ◽

pp. 274-278 ◽

Cited By ~ 7

Author(s):

Paolo Rovero ◽

Maria Pellegrini ◽

Armida Di Fenza ◽

Stefania Meini ◽

Laura Quartara ◽

...

Keyword(s):

Agonist Activity ◽

Structural Requirements ◽

B1 Receptor ◽

Kinin B1 Receptor

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The Effect of Fluoxetine and Ibuprofen on BCG-Induced Alteration in Pain Sensitivity in Mice

QJM ◽

10.1093/qjmed/hcab114.002 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Heba H El-Morsy ◽

Wesam El-Bakly ◽

Amany H Hasanin ◽

May Hamza ◽

M Abdel-Bary

Keyword(s):

Drinking Water ◽

Mechanical Allodynia ◽

Formalin Test ◽

Forced Swim Test ◽

Tail Suspension Test ◽

Control Group ◽

Base Line ◽

Immobility Time ◽

Long Time ◽

Incisional Pain

Abstract Clinical observations recognized the co-existence and interactions of pain and depression a long time, ago. The aim of this work was to study the effect of ibuprofen and fluoxetine on BCGinduced depressive-like behaviour, on formalin-induced pain, as well as on mechanical allodynia after planter incision in mice. BCG induced a depressive behaviour that was seen in the forced swim test (FST) and the tail suspension test (TST). It also induced a decrease in pain-related behaviour in the formalin test, and an increase in the baseline in mechanical allodynia test compared to the control group. Fluoxetine (80 mg/L of drinking water) showed a significant decrease in the immobility time in the FST and TST and enhanced pain related behaviour in formalin test in the BCG-inoculated group. However, it did not affect the increase in the pain threshold in the planter incision allodynia model. Adding ibuprofen to drinking water (0.2 g/L of drinking water), reversed the depressive like behaviour induced by BCG and enhanced pain-related behaviour in formalin test, in both the total pain-related behaviour and phase 2. It also prevented the increase in the base line induced by BCG. On the other hand, the incisional pain model was not affected by BCG inoculation except at the 2-hour time point, where it showed hypoalgesia, as well.

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