記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/brain/awaf182

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Persistent physical and psychological stress is highly relevant to the development of chronic muscle pain; however, the neural mechanisms underlying stress-induced hyperalgesia remain largely unknown. This study aimed to elucidate the peripheral and spinal mechanisms of stress-induced muscle hyperalgesia using a rat model developed under multiple continuous stress (MCS) by keeping rats in a cage filled with shallow water (1.5 cm in depth) for 5 or 6 days. In the MCS rats, intramuscular injection of capsaicin (300 μM, 50 μL), which activates TRPV1-positive muscular C-fiber nociceptors, increased pain-related facial expressions scored using a rat grimace scale. Intramuscular capsaicin injections induced significant c-Fos expression throughout the ipsilateral spinal dorsal horn (laminae I–VI) at segments L3–L5 in rats exposed to MCS, when compared to naïve control rats. Increased c-Fos expression was also observed on the contralateral side in the MCS group. Single-fiber electrophysiological recordings using ex vivo muscle-nerve preparations revealed that neither the general characteristics nor the responsiveness of muscular C-fibers to noxious stimuli were altered in the MCS group. These results indicate that spinal nociceptive hypersensitivity is associated with muscle pain induced by MCS. However, it is unlikely to be mediated by altered responses to muscular C-fiber nociceptors.

DOI： 10.1016/j.neures.2025.02.009

Open Access

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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）  

BACKGROUND: Fibromyalgia is characterized by chronic pain, fatigue, and other somatic symptoms. We have recently revealed that proprioceptor hyperactivation induces chronic pain in a rat model of myalgic encephalomyelitis. The present study explores whether similar proprioceptor-induced pain is elicited in a mouse model of fibromyalgia. METHODS: Repeated cold stress (RCS) was used as a fibromyalgia model. Pain behavior was examined using the von Frey test, and neuronal activation was examined immunohistochemically as activating transcription factor (ATF)3 expression. The Atf3:BAC transgenic mouse, in which mitochondria in hyperactivated neurons are specifically labeled by green fluorescent protein, was used to trace the activated neuronal circuit. PLX3397 (pexidartinib) was used for microglial suppression. RESULTS: RCS elicited long-lasting pain in mice. ATF3, a marker of cellular hyperactivity and injury, was expressed in the lumbar dorsal root ganglion (DRG) 2 days after RCS initiation; the majority of ATF3-expressing DRG neurons were tropomyosin receptor kinase C- and/or vesicular glutamate transporter 1-positive proprioceptors. Microglial activation and increased numbers of microglia were observed in the medial part of the nucleus proprius 5 days after RCS initiation, and in the dorsal region of the ventral horn 7 days after RCS. In the ventral horn, only a subset of motor neurons was positive for ATF3; these neurons were surrounded by activated microglia. A retrograde tracer study revealed that ATF3-positive motor neurons projected to the intrinsic muscles of the foot (IMF). Using Atf3:BAC transgenic mice, we traced hyperactivated neuronal circuits along the reflex arc. Green fluorescent protein labeling was observed in proprioceptive DRG neurons and their processes originating from the IMF, as well as in motor neurons projecting to the IMF. Microglial activation was observed along this reflex arc, and PLX3397-induced microglial ablation significantly suppressed pain behavior. CONCLUSION: Proprioceptor hyperactivation leads to local microglial activation along the reflex arc; this prolonged microglial activation may be responsible for chronic pain in the present model. Proprioceptor-induced microglial activation might be the common cause of chronic pain in both the fibromyalgia and myalgic encephalomyelitis models, although the experimental models are different.

DOI： 10.1186/s12974-024-03018-6

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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）  

Fibromyalgia (FM) is a debilitating disease characterized by generalized and persistent musculoskeletal pain. Although central mechanisms are strongly implicated in the pathogenesis of FM, the involvement of peripheral mechanisms is poorly understood. To understand the peripheral nociceptive mechanisms, we examined muscular nociceptors in an FM model, which was made by exposing rats to repeated cold stress (RCS). A single muscle C-fiber nociceptors were identified through the teased fiber technique using ex vivo muscle-nerve preparations. Response properties of C-fibers to noxious stimuli were systematically analyzed. Messenger RNA expression of neurotrophic factors and inflammatory mediators were also studied in the muscle. In the RCS group, the mechanical response threshold of C-fibers, measured using a ramp mechanical stimulus, was significantly decreased, and the response magnitude was significantly increased in the RCS group when compared with the SHAM group, where the environmental temperature was not altered. The general characteristics of C-fibers and the responsiveness to noxious cold and heat stimuli were similar between the two groups. Messenger RNAs of neurotrophic factors and inflammatory mediators were not changed in the muscle during and after RCS. These results suggest that augmentation of the mechanical response of muscle C-fiber nociceptors contributes to hyperalgesia in the RCS model.

DOI： 10.1016/j.neures.2019.12.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Delayed onset muscle soreness (DOMS) is characterized by mechanical hyperalgesia after lengthening contractions (LC). It is relatively common and causes disturbance for many people who require continuous exercise, yet its molecular and peripheral neural mechanisms are poorly understood. METHODS: We examined whether muscular myelinated Aδ-fibres, in addition to unmyelinated C-fibres, are involved in LC-induced mechanical hypersensitivity, and whether acid-sensing ion channel (ASIC)-3 expressed in thin-fibre afferents contributes to this type of pain using a rat model of DOMS. The peripheral contribution of ASIC3 was investigated using single-fibre electrophysiological recordings in extensor digitorum longus muscle-peroneal nerve preparations in vitro. RESULTS: Behavioural tests demonstrated a significant decrease of the muscular mechanical withdrawal threshold following LC to ankle extensor muscles, and it was improved by intramuscular injection of APETx2 (2.2 μM), a selective blocker of ASIC3. The lower concentration of APETx2 (0.22 µM) and its vehicle had no effect on the threshold. Intramuscular injection of APETx2 (2.2 μM) in naïve rats without LC did not affect the withdrawal threshold. In the ankle extensor muscles that underwent LC one day before the electrophysiological recordings, the mechanical response of Aδ- and C-fibres was significantly facilitated (i.e. decreased response threshold and increased magnitude of the response). The facilitated mechanical response of the Aδ- and C-fibres was significantly suppressed by selective blockade of ASIC3 with APETx2, but not by its vehicle. CONCLUSIONS: These results clearly indicate that ASIC3 contributes to the augmented mechanical response of muscle thin-fibre receptors in delayed onset muscular mechanical hypersensitivity after LC. SIGNIFICANCE: Here, we show that not only C- but also Aδ-fibre nociceptors in the muscle are involved in mechanical hypersensitivity after lengthening contractions, and that acid-sensing ion channel (ASIC)-3 expressed in the thin-fibre nociceptors is responsible for the mechanical hypersensitivity. ASIC3 might be a novel pharmacological target for pain after exercise.

DOI： 10.1002/ejp.1454

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総ページ数：183p   記述言語：日本語

CiNii Research

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総ページ数：xiii, 264p   記述言語：日本語

CiNii Research

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掲載種別：速報，短報，研究ノート等（学術雑誌）  

DOI： 10.15063/rigaku.12243

担当区分：筆頭著者  

記述言語：日本語   出版者・発行元：(一社)日本疲労学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：新潟医療福祉学会  

CiNii Research

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記述言語：日本語   出版者・発行元：新潟医療福祉学会  

CiNii Research

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開催年月日： 2025年10月

会議種別：口頭発表（一般）  

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開催年月日： 2025年9月

会議種別：ポスター発表  

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開催年月日： 2024年10月

会議種別：口頭発表（一般）  

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開催年月日： 2024年7月

会議種別：ポスター発表  

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開催年月日： 2024年3月

会議種別：ポスター発表  

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