TRPA1 activation mediates nociception behaviors in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis

Dalenogare, Diéssica Padilha; Theisen, Maria Carolina; Peres, Diulle Spat; Fialho, Maria Fernanda Pessano; Lückemeyer, Débora Denardin; Antoniazzi, Caren Tatiane de David; Kudsi, Sabrina Qader; Ferreira, Marcella de Amorim; Ritter, Camila; Ferreira, Juliano; Oliveira, Sara Marchesan; Trevisan, Gabriela

doi:10.1016/j.expneurol.2020.113241

Cited by 17 publications

(21 citation statements)

References 76 publications

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“…Reactive oxygen species-induced peroxidation of polyunsaturated fatty acids produces 4-HNE, which contributes to pain-like behavior in rodents [ 27 ]. To characterize the direct effect of 4-HNE on the mechanical nociceptive threshold, we administered 4-HNE in different doses (15–120 nmol/paw) ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

et al. 2021

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Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

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Section: Resultsmentioning

confidence: 99%

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

et al. 2021

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“…injection) in neuropathic pain-like behaviours induced by relapsing-remitting (RR) EAE and PMS-EAE, two different MS mouse models. The antinociceptive effects of these compounds was detected for 1–2 h in these MS models [ 43 , 44 ]. Apocynin and α-lipoic acid, when administered in mice in the doses used in this study, showed an antinociceptive effects for 1–2 h in other pain models [ 9 , 94 ].…”

Section: Discussionmentioning

confidence: 99%

“…and apocynin (W508454, Sigma-Aldrich, St. Louis, MO, USA; NADPH oxidase inhibitor, 100 mg/kg, i.g.) by oral gavage [ 9 , 43 , 44 ]. All treatments, except olcegepant, had a vehicle group that received the correspondent vehicle (dimethyl sulfoxide-DMSO (472301, Sigma-Aldrich, St. Louis, MO, USA) 1% in isotonic saline 0.9%, 10 mL/kg) and periorbital mechanical threshold evaluated from 1 up to 3 or 4 h after vehicle or compound administration.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, our group described the relation between the development of neuropathic pain-like behaviours and TRPA1 activation induced by two different MS mouse models: the PMS-EAE and the relapsing-remitting multiple sclerosis (RR-EAE) models [ 43 , 44 ]. Thus, our main purpose was to optimise the development of PMA in a PMS-EAE model and detect the role of TRPA1 in this nociceptive behaviour.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

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“…In the first part, 10 rats were used as bone cancer pain models and randomly divided into two groups: BCP + normal saline (BCP, n = 5) and BCP + A967079 (n = 5). All drugs were injected intravenously at 9 am on the 7th postoperative day only (A967079, TRPA1 antagonist, 10 mg/kg, 10 µl; normal saline 10 µl) (18,19).…”

Section: Animalsmentioning

confidence: 99%

The TRPA1 Channel Mediates Mechanical Allodynia and Thermal Hyperalgesia in a Rat Bone Cancer Pain Model

et al. 2021

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Background: Bone cancer pain (BCP) significantly affects patient quality of life, results in great bodily and emotional pain, and creates difficulties in follow-up treatment and normal life. Transient receptor potential ankyrin 1 (TRPA1) is an essential transduction ion channel related to neuropathic and inflammatory pain. However, the role of TRPA1 in BCP remains poorly understood. This study aimed to explore the relationship between TRPA1 and BCP.Methods: A BCP model was induced by Walker256 cells to the left tibia. The sham group was induced by normal saline to the left tibia. Thereafter, pain behaviors and TRPA1 expression between the BCP group and the sham group were observed on the 14th day of modeling. The TRPA1 antagonist A967079 (10 mg/kg) was injected via tail vein. TRPA1 antisense oligodeoxynucleotide (AS-ODN, 5 nmol/10 μl) and missense oligodeoxynucleotide (MS-ODN, 5 nmol/10 μl) were intrathecally delivered via a mini-osmotic pump for 5 consecutive days to assess the effect of TRPA1 on BCP. Behavioral tests were assessed preoperatively and postoperatively. Real-time quantitative PCR and western blot analyses were used to measure TRPA1 levels among the different groups.Results: The BCP model was successfully established via X-ray and pathological sections at 14 days. Compared to the sham group, the BCP group was more sensitive to mechanical stimuli, cool stimuli and hot stimuli. Intravenously injected A967079 can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Moreover, AS-ODN can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Additionally, relative mRNA and protein expression of TRPA1 in the BCP group were much higher than those in the sham group (14.55 ± 1.97 vs. 1 ± 0.04, P < 0.01). Compared to the BCP group, the relative mRNA and protein expression of TRPA1 in the BCP+AS-ODN group was reduced (14.55 ± 1.97 vs. 2.59 ± 0.34, P < 0.01).Conclusions: The TRPA1 channel mediates mechanical allodynia and thermal hyperalgesia in a rat BCP model.

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TRPA1 activation mediates nociception behaviors in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis

Cited by 17 publications

References 76 publications

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

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

The TRPA1 Channel Mediates Mechanical Allodynia and Thermal Hyperalgesia in a Rat Bone Cancer Pain Model

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