Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

Dalenogare, Diéssica Padilha; Ritter, Camila; Bellinaso, Fernando; Kudsi, Sabrina Qader; Pereira, Gabriele Cheiran; Fialho, Maria Fernanda Pessano; Lückemeyer, Débora Denardin; Antoniazzi, Caren Tatiane de David; Landini, Lorenzo; Ferreira, Juliano; Bochi, Guilherme Vargas; Oliveira, Sara Marchesan; Logu, Francesco De; Nassini, Romina; Geppetti, Pierangelo; Trevisan, Gabriela

doi:10.3390/ph14080831

Cited by 13 publications

(15 citation statements)

References 114 publications

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“…Emerging evidence indicates that TRPA1 is a molecular ionotropic receptor mediator [1] of the neuro-immuno-epithelial interface network [2][3][4] in the lung [5], skin [6] and gut [3,7,8] acting as a "pro-inflammatory hub" [9][10][11]. Absence, dysfunction or inhibition of TRPA1 has been shown to decrease inflammation-related symptoms of psoriasis [6,12,13], rheumatoid arthritis [14], actinic keratosis [15], atopic dermatitis [16][17][18], multiple sclerosis [19][20][21][22][23][24], and its function has been proposed to contribute to a variety of interrelated sensory and inflammatory processes such as inflammatory hyperalgesia [25,26], colitis [7,27], airway inflammation [28,29] and even oxidative stress storm syndromes in COVID-19 [30,31].…”

Section: Introductionmentioning

confidence: 99%

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

et al. 2022

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Transient Receptor Potential Ankyrin 1 (TRPA1) has been reported to influence neuroinflammation and lymphocyte function. We analysed the immune phenotype and activation characteristics of TRPA1-deficient mice (knockout—KO) generated by targeted deletion of the pore-loop domain of the ion channel. We compared TRPA1 mRNA and protein expression in monocyte and lymphocyte subpopulations isolated from primary and secondary lymphatic organs of wild type (WT) and KO mice. qRT-PCR and flow cytometric studies indicated a higher level of TRPA1 in monocytes than in lymphocytes, but both were orders of magnitude lower than in sensory neurons. We found lower CD4+/CD8+ thymocyte ratios, diminished CD4/CD8 rates, and B cell numbers in the KO mice. Early activation marker CD69 was lower in CD4+ T cells of KO, while the level of CD8+/CD25+ cells was higher. In vitro TcR-mediated activation did not result in significant differences in CD69 level between WT and KO splenocytes, but lower cytokine (IL-1β, IL-6, TNF-α, IL-17A, IL-22, and RANTES) secretion was observed in KO splenocytes. Basal intracellular Ca2+ level and TcR-induced Ca2+ signal in T lymphocytes did not differ significantly, but interestingly, imiquimod-induced Ca2+ level in KO thymocytes was higher. Our results support the role of TRPA1 in the regulation of activation, cytokine production, and T and B lymphocytes composition in mice.

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Section: Introductionmentioning

confidence: 99%

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

et al. 2022

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“…20,27 Recently, using a different model of EAE (progressive EAE), which reproduces a progressive multiple sclerosis model, we detected the role of TRPA1 in periorbital nociception. 16 Thus, the present finding might be considered the first optimizing model of headache-related cephalic allodynia associated with a RR-EAE model. Sumatriptan, a mainstay in the acute treatment of migraine attacks, 6,48 has been found to reduce periorbital nociceptive behaviors in different mouse headache-like models in mice.…”

Section: Discussionmentioning

confidence: 79%

“…49 Facial mechanical allodynia (whisker pad and periorbital region) was detected in a mouse model of progressive MS induced by immunization with the MOG 35-55 antigen and complete Freund adjuvant (CFA). 16,18,19 Besides, we recently showed that TRPA1 mediates plantar mechanical and cold allodynia in a mouse model of RR-EAE induced by the immunization with MOG and Quil A. 15 However, until now, no study has evaluated the development of PMA in a RR-EAE model or evaluated the mechanisms involved in this nociceptive behavior.…”

Section: Introductionmentioning

confidence: 99%

Transient receptor potential ankyrin 1 mediates headache-related cephalic allodynia in a mouse model of relapsing–remitting multiple sclerosis

Dalenogare

Theisen

Peres

et al. 2021

Pain

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Primary headache conditions are frequently associated with multiple sclerosis (MS), but the mechanism that triggers or worsens headaches in patients with MS is poorly understood. We previously showed that the proalgesic transient receptor potential ankyrin 1 (TRPA1) mediates hind paw mechanical and cold allodynia in a relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model in mice. Here, we investigated the development of periorbital mechanical allodynia (PMA) in RR-EAE, a hallmark of headache, and if TRPA1 contributed to this response. RR-EAE induction by injection of the myelin oligodendrocyte peptide fragment 35-55 ) and Quillaja A adjuvant (Quil A) in C57BL/6J female mice elicited a delayed and sustained PMA. The PMA at day 35 after induction was reduced by the calcitonin gene-related peptide receptor antagonist (olcegepant) and the serotonin 5-HT1 B/D receptor agonist (sumatriptan), 2 known antimigraine agents. Genetic deletion or pharmacological blockade of TRPA1 attenuated PMA associated with RR-EAE. The levels of oxidative stress biomarkers (4-hydroxynonenal and hydrogen peroxide, known TRPA1 endogenous agonists) and superoxide dismutase and NADPH oxidase activities were increased in the trigeminal ganglion of RR-EAE mice. Besides, the treatment with antioxidants (apocynin or a-lipoic acid) attenuated PMA. Thus, the results of this study indicate that TRPA1, presumably activated by endogenous agonists, evokes PMA in a mouse model of relapsing-remitting MS.

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“…Here, we have demonstrated that a CGRP receptor antagonist had an antinociceptive and anxiolytic-like effect and reverted the reduced exploratory behavior alterations, showing similar efficacy in male and female ST mice. Olcegepant (BIBN4096BS) was also used to reduce the nociception observed in other models of migraine ( Dalenogare et al, 2021 ). Using a model of repetitive retrain stress, the authors also showed that CGRP signaling may be involved in the migraine-like behaviors detected in this model of stress.…”

Section: Discussionmentioning

confidence: 99%

“…CGRP has been implicated in the pathology of migraine for several decades ( Khan et al, 2019 ), and recent clinical studies have further confirmed CGRP as a protagonist in migraine, using CGRP signaling inhibitors ( Halker Singh et al, 2019 ). A CGRP antagonist (olcegepant, BIBN4096BS) was effective in reducing periorbital allodynia in different models of migraine-like pain ( Dalenogare et al, 2021 ). Moreover, a CGRP injection to the trigeminovascular system caused periorbital mechanical allodynia (PMA) and anxiety-like behavior, which was prolonged in female rats ( Araya et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

et al. 2022

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Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20–30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

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Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

Cited by 13 publications

References 114 publications

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

Transient receptor potential ankyrin 1 mediates headache-related cephalic allodynia in a mouse model of relapsing–remitting multiple sclerosis

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

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