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Maruta T., Kouroki S., Kurogi M., Hidaka K., Koshida T., Miura A., Nakagawa H., Yanagita T., Takeya R., Tsuneyoshi I.
Journal of Neuroscience Research 102 ( 10 ) e25386 2024年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Neuroscience Research
Voltage-gated sodium channels, including NaV1.7, NaV1.8, and NaV1.9, play important roles in pain transmission and chronic pain development. However, the specific mechanisms of their action remain unclear, highlighting the need for in vivo stimulation studies of these channels. Optogenetics, a novel technique for targeting the activation or inhibition of specific neural circuits using light, offers a promising solution. In our previous study, we used optogenetics to selectively excite NaV1.7-expressing neurons in the dorsal root ganglion of mice to induce nocifensive behavior. Here, we further characterize the impact of nocifensive behavior by activation of NaV1.7, NaV1.8, or NaV1.9-expressing neurons. Using CRISPR/Cas9-mediated homologous recombination, NaV1.7–iCre, NaV1.8–iCre, or NaV1.9–iCre mice expressing iCre recombinase under the control of the endogenous NaV1.7, NaV1.8, or NaV1.9 gene promoter were produced. These mice were then bred with channelrhodopsin-2 (ChR2) Cre–reporter Ai32 mice to obtain NaV1.7–ChR2, NaV1.8–ChR2, or NaV1.9–ChR2 mice. Blue light exposure triggered paw withdrawal in all mice, with the strongest response in NaV1.8–ChR2 mice. These light sensitivity differences observed across NaV1.x–ChR2 mice may be dependent on ChR2 expression or reflect the inherent disparities in their pain transmission roles. In conclusion, we have generated noninvasive pain models, with optically activated peripheral nociceptors. We believe that studies using optogenetics will further elucidate the role of sodium channel subtypes in pain transmission.
DOI： 10.1002/jnr.25386
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透析用バスキュラーアクセスカテーテルが上行腰静脈に迷入し腸腰筋血腫を呈した1症例 査読あり
古澤 高廣, 矢野 武志, 菓子野 里奈, 吉海 瑞穂, 越田 智広, 與那覇 哲, 谷口 正彦, 恒吉 勇男
日本集中治療医学会雑誌 30 ( 1 ) 23 - 24 2023年1月
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Koshida T., Maruta T., Tanaka N., Hidaka K., Kurogi M., Nemoto T., Yanagita T., Takeya R., Tsuneyoshi I.
Acta Medica Okayama 77 ( 4 ) 359 - 364 2023年
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Medica Okayama
Pulsed radiofrequency (PRF) is a safe method of treating neuropathic pain by generating intermittent electric fields at the needle tip. Resiniferatoxin (RTX) is an ultrapotent agonist of transient receptor potential vanilloid subtype-1 (TRPV1) receptors. We investigated the mechanism of PRF using a rat model of RTX-induced neuropathic pain. After administering RTX intraperitoneally, PRF was applied to the right sciatic nerve. We observed the changes in TRPV1, calcitonin gene-related peptide (CGRP), and brain-derived neurotrophic factor (BDNF) in the dorsal root ganglia by western blotting. Expressions of TRPV1 and CGRP were significantly lower in the contralateral (RTX-treated, PRF-untreated) tissue than in control rats (p<0.0001 and p<0.0001, respectively) and the ipsilateral tissues (p<0.0001 and p<0.0001, respectively). BDNF levels were significantly higher in the contralateral tissues than in the control rats (p<0.0001) and the ipsilateral tissues (p<0.0001). These results suggest that, while TRPV1 and CGRP are decreased by RTX-induced neuronal damage, increased BDNF levels result in pain development. PRF may promote recovery from neuronal damage with concomitant restoration of TRPV1 and CGRP, and exert its analgesic effect by reversing BDNF increase. Further research is required to understand the role of TRPV1 and CGRP restoration in improving mechanical allodynia.
DOI： 10.18926/AMO/65741
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Maruta T., Hidaka K., Kouroki S., Koshida T., Kurogi M., Kage Y., Mizuno S., Shirasaka T., Yanagita T., Takahashi S., Takeya R., Tsuneyoshi I.
PLoS ONE 17 ( 10 October ) e0275751 2022年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
In small and large spinal dorsal root ganglion neurons, subtypes of voltage-gated sodium channels, such as NaV1.7, NaV1.8, and NaV1.9 are expressed with characteristically localized and may play different roles in pain transmission and intractable pain development. Selective stimulation of each specific subtype in vivo may elucidate its role of each subtype in pain. So far, this has been difficult with current technology. However, Optogenetics, a recently developed technique, has enabled selective activation or inhibition of specific neural circulation in vivo. Moreover, optogenetics had even been used to selectively excite NaV1.8-expressing dorsal root ganglion neurons to induce nocifensive behavior. In recent years, genetic modification technologies such as CRISPR/Cas9 have advanced, and various knock-in mice can be easily generated using such technology. We aimed to investigate the effects of selective optogenetic activation of NaV1.7-expressing afferents on mouse behavior. We used CRISPR/Cas9-mediated homologous recombination to generate bicistronic NaV1.7–iCre knock-in mice, which express iCre recombinase under the endogenous NaV1.7 gene promoter without disrupting NaV1.7. The Cre-driver mice were crossed with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain NaV1.7iCre/+;Ai32/+, NaV1.7iCre/iCre;Ai32/+, NaV1.7iCre/+;Ai32/Ai32, and NaV1.7iCre/iCre;Ai32/Ai32 mice. Compared with wild–type mice behavior, no differences were observed in the behaviors associated with mechanical and thermal stimuli exhibited by mice of the aforementioned genotypes, indicating that the endogenous NaV1.7 gene was not affected by the targeted insertion of iCre. Blue light irradiation to the hind paw induced paw withdrawal by mice of all genotypes in a light power-dependent manner. The threshold and incidence of paw withdrawal and aversive behavior in a blue-lit room were dependent on ChR2 expression level; the strongest response was observed in NaV1.7iCre/iCre;Ai32/Ai32 mice. Thus, we developed a non-invasive pain model in which peripheral nociceptors were optically activated in free-moving transgenic NaV1.7–ChR2 mice.
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Hidaka K., Maruta T., Koshida T., Kurogi M., Kage Y., Kouroki S., Shirasaka T., Takeya R., Tsuneyoshi I.
Molecular Pain 18 17448069221089784 2022年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Pain
Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.
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選択的血漿交換療法が奏効した抗体陰性視神経脊髄炎の１症例．
越田智広，山下幸貴，與那覇 哲，内村修二，興梠聡志，米良 舞，谷口正彦，恒吉勇男
第52回日本集中治療医学会学術集会
開催年月日： 2025年3月14日 - 2025年3月16日
記述言語：日本語 会議種別：ポスター発表
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光応答性疼痛マウスに持続的な光照射をすることで作製した神経障害性疼痛モデルの検討．
興梠聡志，丸田豊明，日髙康太郎，越田智広，恒吉勇男
第46回日本疼痛学会 2024年11月17日
開催年月日： 2024年11月16日 - 2024年11月17日
記述言語：日本語 会議種別：口頭発表（一般）
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高度肥満が原因で緊急開腹術後に呼吸管理に難渋した１例．
丸田豊明、興梠聡志、米良舞、内村修二、越田智広、與那覇哲、山下幸貴、谷口正彦、恒吉勇男
第39回日本救命医療学会総会・学術集会 2024年9月21日
開催年月日： 2024年9月21日
記述言語：日本語 会議種別：口頭発表（一般）
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光応答性疼痛マウスは脊髄後根神経節でのNaV1.7増加をスクリーニングできる 〜FK506誘発性疼痛モデルでの検証〜（優秀演題）．
丸田豊明，興梠聡志，白石成二，日髙康太郎，越田智広，恒吉勇男
日本麻酔科学会第71回学術集会 2024年6月6日
開催年月日： 2024年6月6日 - 2024年6月8日
記述言語：日本語 会議種別：ポスター発表
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帯状疱疹後神経痛モデルラットにおける高周波パルス療法の作用機序の検討．
日髙康太郎，丸田豊明，越田智広，興梠聡志，白阪哲朗，恒吉勇男
第43回日本疼痛学会
開催年月日： 2021年12月10日 - 2021年12月11日
記述言語：日本語 会議種別：口頭発表（一般）