Orthodontic force-induced oxidative stress in the periodontal tissue and dental pulp elicits nociception via activation/sensitization of TRPA1 on nociceptive fibers

Morii, Aoi; Miyamura, Yuichi; Sago, Misa I.; Mizuhara, Masahiro; Shikayama, Takemi; Naniwa, Mako; Hitomi, Suzuro; Ujihara, Izumi; Kuroishi, Kayoko N.; Gunjigake, Kaori; Shiga, Momotoshi; Morimoto, Yasuhiro; Kawamoto, T.; Ono, Kentaro

doi:10.1016/j.freeradbiomed.2019.12.016

Cited by 24 publications

(27 citation statements)

References 80 publications

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“…Indeed, here we found that the mechanical activity of hTRPA1, which is partially oxidized (9), was abolished by the thiol reducing agent TCEP that also neutralized the U-shaped thermosensitivity of purified hTRPA1 (9). Oxidants including H2O2 also sensitize TRPA1 heat responses in cells and isolated tissues (9,15), and a recent study showed H2O2 sensitization of TRPA1-mediated mechanical responses in mouse trigeminal sensory neurons when exposed to a hyperosmotic solution (16). Taken together, it is suggested that oxidative stress and perhaps other environmental factors (e.g., pH, Ca 2+ , polyphosphates) alone or in combination can shape the response to mechanical stimuli by shifting hTRPA1 into a force-to-lipid sensitive protein conformation.…”

Section: Discussionsupporting

confidence: 56%

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Moparthi

Zygmunt

2020

Preprint

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The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an intrinsic chemo-and thermo-sensitive ion channel with distinct sensory signaling properties. Although a role of TRPA1 in mammalian mechanosensory transduction in vivo seems likely, it remains to be shown that TRPA1 has the inherent capability to respond to mechanical stimuli. Here we have used the patch-clamp technique to study the response of human purified TRPA1 (hTRPA1), reconstituted into artificial lipid bilayers, to changes in bilayer pressure. We report that hTRPA1 responded with increased single-channel open probability (Po) within the applied pressure interval of 7.5 to 60 mmHg with a half maximum Po (P50) value of 38.0 ± 2.3 mmHg. The Po value reached a maximum close to 1 (0.87 ± 0.02) at 60 mmHg. Within the same pressure interval, hTRPA1 without its N-terminal ankyrin repeat domain (Δ1-688 hTRPA1) responded fully opened (0.99 ± 0.01) at 60 mmHg and with a P50 value of 39.0 ± 1.1 mmHg. The pressure-evoked responses of hTRPA1 and Δ1-688 hTRPA1 at 45 mmHg were inhibited by the TRPA1 antagonist HC030031, and the activity of purified hTRPA1 at 45 mmHg was abolished by the thiol reducing agent tris(2-carboxyethyl)phosphine (TCEP). In conclusion, hTRPA1 is an inherent mechanosensitive ion channel gated by force-from-lipids. The hTRPA1 mechanosensitivity is dependent on the redox environment, and it is suggested that oxidative stress shifts hTRPA1 into a protein conformation sensitive to mechanical stimuli.

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Section: Discussionsupporting

confidence: 56%

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Moparthi

Zygmunt

2020

Preprint

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“…Two members of the TRP superfamily are TRPA1 and TRPV1 channels, and they are also activated by OS [8,13]. The involvements of TRPA1 and TRPV1 on the GTNmediated migraine and pain models were recently reported [55][56][57]. Within the OS-dependent-activated TRP channels, TRPM2 is first discovered channel [15,16].…”

Section: Discussionmentioning

confidence: 99%

Involvement of TRPM2 in the Neurobiology of Experimental Migraine: Focus on Oxidative Stress and Apoptosis

Yazğan

Nazıroğlu

2021

Mol Neurobiol

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Excessive Ca 2+ influx and mitochondrial oxidative stress (OS) of trigeminal ganglia (TG) have essential roles in the etiology of migraine headache and aura. The stimulation of TRPM2 channel via the generation of OS and ADP-ribose (ADPR) induces pain, inflammatory, and oxidative neurotoxicity, although its inhibition reduces the intensity of pain and neurotoxicity in several neurons. However, the cellular and molecular effects of TRPM2 in the TG of migraine model (glyceryl trinitrate, GTN) on the induction of pain, OS, apoptosis, and inflammation remain elusive. GTN-mediated increases of pain intensity, apoptosis, death, cytosolic reactive oxygen species (ROS), mitochondrial ROS, caspase -3, caspase -9, cytosolic Ca 2+ levels, and cytokine generations (TNF-α, IL-1β, and IL-6) in the TG of TRPM2 wild-type mouse were further increased by the TRPM2 activation, although they were modulated by the treatments of GSH, PARP-1 inhibitors (PJ34 and DPQ), and TRPM2 blockers (ACA and 2APB). However, the effects of GTN were not observed in the TG of TRPM2 knockout mice. The current data indicate that the maintaining activation of TRPM2 is not only important for the quenching OS, inflammation, and neurotoxicity in the TG neurons of mice with experimental migraine but also equally critical to the modulation of GTN-induced pain.

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“…The mechanical sensitivity of TRPA1 is indirectly enhanced by endothelin-1 [16] and directly enhanced by the bacterial toxin lipopolysaccharide [31]. Our recent study demonstrated that TRPA1 contributes to the hypertonic stimulation-induced Ca 2+ response in dissociated trigeminal ganglion neurons [32]. In the present study, hypertonic stimulation-induced and AITC-induced Ca 2+ responses were suppressed by long-term preincubation with Tmc, suggesting that TRPA1 suppression following the long-term effect of Tmc on peripheral nerves inhibits oral ulcerative mucositis-induced mechanical allodynia.…”

Section: Discussionmentioning

confidence: 84%

“…Endothelin and bacterial toxins sensitize mechanosensitive TRPA1 channels in nociceptive nerves [16,31]. Our recent study reported that the hypertonic stimulation-induced Ca 2+ response in dissociated trigeminal ganglion neurons was caused by TRPA1 activation [32]. Therefore, we investigated the effect of Tmc on the hypertonic stimulation-induced Ca 2+ response in sensory neurons (Figure 4E).…”

Section: Anti-allodynic Mechanism Of a Steroid Containing Ointment In Oum Ratsmentioning

confidence: 99%

Analgesic Mechanisms of Steroid Ointment against Oral Ulcerative Mucositis in a Rat Model

Naniwa

Nakatomi

Hitomi

et al. 2021

IJMS

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Despite the long history of use of steroid ointments for oral mucositis, the analgesic mechanism has not been fully elucidated. In this study, we examined the effects of triamcinolone acetonide (Tmc) on oral ulcerative mucositis-induced pain in conscious rats by our proprietary assay system. Based on evaluations of the physical properties and retention periods in the oral mucosa of human volunteers and rats, we selected TRAFUL® ointment as a long-lasting base. In oral ulcerative mucositis model rats, TRAFUL® with Tmc suppressed cyclooxygenase-dependent inflammatory responses with upregulations of glucocorticoid receptor-induced anti-inflammatory genes and inhibited spontaneous nociceptive behavior. When an ointment with a shorter residual period was used, the effects of Tmc were not elicited or were induced to a lesser extent. Importantly, TRAFUL® with Tmc also improved oral ulcerative mucositis-induced mechanical allodynia, which has been reported to be independent of cyclooxygenase. Ca2+ imaging in dissociated trigeminal ganglion neurons showed that long-term preincubation with Tmc inhibited the hypertonic stimulation-induced Ca2+ response. These results suggest that the representative steroid Tmc suppresses oral ulcerative mucositis-induced pain by general anti-inflammatory actions and inhibits mechanical sensitivity in peripheral nerves. For drug delivery, long-lasting ointments such as TRAFUL® are needed to sufficiently induce the therapeutic effects.

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Orthodontic force-induced oxidative stress in the periodontal tissue and dental pulp elicits nociception via activation/sensitization of TRPA1 on nociceptive fibers

Cited by 24 publications

References 80 publications

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Involvement of TRPM2 in the Neurobiology of Experimental Migraine: Focus on Oxidative Stress and Apoptosis

Analgesic Mechanisms of Steroid Ointment against Oral Ulcerative Mucositis in a Rat Model

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