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Cited by 22Pain Mechanisms and TreatmentsFibromyalgia and Chronic Fatigue Syndrome ResearchPain Management and Treatment

Repeated cold stress, an animal model for fibromyalgia, elicits proprioceptor-induced chronic pain with microglial activation in mice

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Wakatsuki, Koji, Kiryu-Seo, Sumiko, Yasui, Masaya, Yokota, Hiroki, Kida, Haruku, Konishi, Hiroyuki, Kiyama, Hiroshi·2024·Journal of Neuroinflammation
DOI 10.1186/s12974-024-03018-6PMC PMC10795366
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Abstract

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.

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  • Glial cell activation and excessive proliferation represent a critical pathway in NPP development.

    “indicating that glial cell activation and excessive proliferation represent a critical pathway in NPP development of NPP (133).”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [133]

    The Results sections on microglial activation and its suppression report increased numbers of activated spinal microglia after repeated cold stress in mice, and reduced pain behavior when microglia were suppressed. The Discussion suggests that subsequent microglial activation may lead to chronic pain. The paper studies a fibromyalgia model, however, not neuropathic pain (NPP), and increased microglial numbers do not establish excessive proliferation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Depletion of microglia using PLX3397 alleviates RCS-induced hyperalgesia.

    “Depletion of microglia using PLX3397 (pexidartinib) alleviated RCS-induced hyperalgesia”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [133]

  • In the spinal cord of a mouse model of FMS induced by repeated cold stress, neuronal hyperactivation is accompanied by activation and proliferation of surrounding microglia.

    “In the spinal cord of a mouse model of FMS induced by repeated cold stress (RCS), neuronal hyperactivation was accompanied by the activation and proliferation of surrounding microglia.”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [133]

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Authors
Wakatsuki, K., Kiryu-Seo, S., Yasui, M., Yokota, H., Kida, H., Konishi, H., & Kiyama, H.
Affiliations
  • Nagoya University (JP)
  • Tokoha University (JP)
  • Meijo University (JP)
Corresponding author
Kiyama, Hiroshi
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2024-01-18
Volume
21
Issue
1
Pages
25-25
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-024-03018-6
PMC
PMC10795366
OpenAlex
W4390983873
Cited by
22
References
2
Citations by year
2026: 8 · 2025: 10 · 2024: 4
FWCI
6.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
KAKENHI (25430036, 21K11688, 16K15170)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
fibromyalgia, chronic pain, microglial activation, ATF3, dorsal root ganglion neurons, ventral horn motor neurons, intrinsic foot muscles, reflex arc, PLX3397, chronic fatigue syndrome, animal models
MeSH terms
Aminopyridines, Animals, Disease Models, Animal, Fibromyalgia, Ganglia, Spinal, Pyrroles, Fatigue Syndrome, Chronic, Microglia, Green Fluorescent Proteins, Mice, Rats, Cold-Shock Response, Chronic Pain

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