Language：English   Publishing type：Research paper (scientific journal)  

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons in ALS model mice express activating transcription factor 3 (ATF3), a well-known marker of nerve injury and disease progression, suggesting that both types of neurons respond to ALS pathology. However, it remains unknown why only DRG neurons are resilient to ALS pathological damage. To address this issue, we used a nerve injury model in combination with unique injury-induced genetically engineered mice, in which genetic control with an Atf3 regulatory element enables proteasome ablation and mitochondrial visualization specifically in damaged neurons. Using the strategy, we found that DRG neurons are resistant to damage in proteasome-deficient conditions, whereas spinal motor neurons degenerate in the same conditions. This might be because DRG neurons lack the typical axon initial segment (AIS), which normally exists in mature neurons and acts as a gate for the selective transport of cargo to axons. The absence of a typical AIS in DRG neurons facilitated increased entry of mitochondria into the axon upon injury, with or without proteasome function. In contrast, damaged motor neurons lacking the proteasome failed to disassemble the AIS, which prevented increased mitochondrial influx into axons and led to energy depletion and degeneration. In the absence of the AIS, DRG neurons in the ALS mouse model are able to deliver sufficient mitochondria into the axon to prevent pathological damage. However, impaired proteasome function in ALS motor neurons results in retention of the AIS gate and failure of mitochondrial transport to axons. This is a possible reason why DRG neurons have greater resilience to ALS pathological damage compared with spinal motor neurons. Collectively, this study opens new directions for the understanding of neurodegenerative diseases at early stages of disturbed protein homeostasis.

DOI： 10.1093/brain/awaf182

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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 (1.5cm in depth) for 5 or 6 days. In the MCS rats, intramuscular injection of capsaicin (300μM, 50μL), 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

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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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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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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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Total pages：183p   Language：Japanese

CiNii Research

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Total pages：xiii, 264p   Language：Japanese

CiNii Research

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Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.15063/rigaku.12243

Authorship：Lead author  

Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：新潟医療福祉学会  

CiNii Research

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Language：Japanese   Publisher：新潟医療福祉学会  

CiNii Research

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Event date： 2025.10

Presentation type：Oral presentation (general)  

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Event date： 2025.9

Presentation type：Poster presentation  

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Event date： 2024.10

Presentation type：Oral presentation (general)  

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Event date： 2024.7

Presentation type：Poster presentation  

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Event date： 2024.3

Presentation type：Poster presentation  

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