Mechanisms underlying immobilization‐induced muscle pain in rats

Oga, Satoshi; Goto, Kyo; Sakamoto, Juichi; Honda, Yoshiyuki; Sasaki, Ryo; Ishikawa, Kumiko; Kataoka, Hideki; Nakano, Jun; Origuchi, Tomoki; Okita, Minoru

doi:10.1002/mus.26840

Cited by 13 publications

(17 citation statements)

References 47 publications

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“…In a model of immobilizationinduced pain, CGRP-immunoreactive DRG neurons were found to have a larger cell size on the ipsilateral side of immobilization than on the contralateral side, and the intensity of CGRP immunoreactivity was increased in laminae III-IV but not in laminae I-II [13]. The protein levels of NGF, a neurotrophic factor known to cause hyperalgesia and nociceptor sensitization to mechanical and heat stimuli [17], were increased in the skin and muscle of rats after cast immobilization for 4 weeks [18][19][20]. Cast immobilization decreases the thickness of the epidermis and increases NGF expression and the density of nerve fibers immunoreactive for P2X 3 and TRPV1, which are known to be expressed predominantly in small nerve fibers such as unmyelinated C-fibers [6,20].…”

Section: Open Accessmentioning

confidence: 98%

“…Concerning the heat responses, we detected no changes between the two groups, whereas behavioral nociceptive hypersensitivity to heat was obvious in the immobilization-induced pain model. Recent studies have reported that the expression of NGF proteins is upregulated in the plantar (glabrous) skin and in the gastrocnemius muscle of rats that have undergone hindlimb cast immobilization for 4 weeks [18,19]. NGF is known to induce potent sensitization of nociceptors to mechanical and heat stimuli, resulting in mechanical and heat hyperalgesia [17].…”

Section: Peripheral Mechanisms Of Immobilization-induced Painmentioning

confidence: 99%

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Responses of cutaneous C-fiber afferents and spinal microglia after hindlimb cast immobilization in rats

et al. 2021

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Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization.

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Section: Open Accessmentioning

confidence: 98%

Section: Peripheral Mechanisms Of Immobilization-induced Painmentioning

confidence: 99%

Responses of cutaneous C-fiber afferents and spinal microglia after hindlimb cast immobilization in rats

et al. 2021

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“…Macrophages were divided into M1 macrophages (inflammatory macrophages) and M2 macrophages (anti-inflammatory macrophages), M1 macrophages played a key role of fibrous lesion via IL-1β/TGF-β1 signaling. In our previous study, M1 macrophages increased in 2-week immobilized rat skeletal muscles [ 28 ], we surmised that macrophages accumulation was occurred by M1 macrophages increase in immobilized rat soleus muscles. Also, other previous report showed that physical exercise reduced the M1 macrophage response in myocardial ischemic injury [ 29 ].…”

Section: Discussionmentioning

confidence: 85%

Effect of belt electrode-skeletal muscle electrical stimulation on immobilization-induced muscle fibrosis

et al. 2021

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Purpose Macrophage accumulation in response to decreasing myonuclei may be the major mechanism underlying immobilization-induced muscle fibrosis in muscle contracture, an intervention strategy suppressing these lesions is necessary. Therefore, this research investigated the effect of belt electrode-skeletal muscle electrical stimulation (B-SES), a new electrical stimulation device, to the macrophage accumulation via myonuclei decrease in immobilization-induced muscle fibrosis. Materials and methods 18 Wistar male rats were divided into the control group, immobilization group (with plaster cast fixation to immobilize the soleus muscles in a shortened position for 2 weeks), and B-SES group (with muscle contractile exercise through B-SES during the immobilization period). B-SES stimulation was performed at a frequency of 50 Hz and an intensity of 4.7 mA, muscle contractile exercise by B-SES was applied to the lower limb muscles for 20 minutes/session (twice a day) for 2 weeks (6 times/week). The bilateral soleus muscles were used for histological, immunohistochemical, biochemical, and molecular biological analyses. Results The number of myonuclei was significantly higher in the B-SES group than in the immobilization group, and there was no significant difference between the B-SES and control groups. The cross-sectional area of type I and II myofibers in the immobilization and B-SES groups was significantly lower than that in the control group, and the cross-sectional area of type I myofibers in the B-SES group was higher than that in the immobilization group. However, Atrogin-1 and MuRF-1 mRNA expression in the immobilization and B-SES groups was significantly higher than those in the control group. Additionally, the number of macrophages, IL-1β, TGF-β1, and α-SMA mRNA expression, and hydroxyproline expression was significantly lower in the control and B-SES groups than those in the immobilization group. Conclusion This research surmised that muscle contractile exercise through B-SES prevented immobilization-induced muscle fibrosis, and this alteration suppressed the development of muscle contracture.

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“…Multiple receptors have frequently been associated with the development of musculoskeletal pain. Some of the receptors that have been traditionally associated with increased pain include the NGF receptor TrkA ( Hayashi et al, 2011 ; Queme et al, 2013 ; Oga et al, 2020 ) as well as the ion channel TRPV1. Contrary to our expectations, neither of these receptors showed increased expression after the administration of PEGPH20.…”

Section: Discussionmentioning

confidence: 99%

Disruption of hyaluronic acid in skeletal muscle induces decreased voluntary activity via chemosensitive muscle afferent sensitization in male mice

Queme

Dourson

Hofmann

et al. 2022

eNeuro

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PEGPH20, a human recombinant hyaluronidase, has been proposed as a coadjutant to pancreatic cancer chemotherapy. In early trials, patients reported increased widespread muscle pain as the main adverse reaction to PEGPH20. To understand how PEGPH20 caused musculoskeletal pain, we systemically administered PEGPH20 to male mice and measured voluntary wheel activity and pain-related behaviors. These were paired with ex vivo electrophysiology of primary sensory neurons, whole DRG real-time PCR, and immunohistochemistry of hindpaw muscle. PEGPH20 induced significantly lower wheel running, compared with vehicle-treated animals, and decreased mechanical withdrawal thresholds 5 d after PEGPH20 injections. Chemo-sensory muscle afferents showed increased responses to noxious chemical stimulation of their receptive fields (RFs) in the PEGPH20-treated group. This was correlated with upregulation of the NGF receptor TrkA, the transient receptor potential vanilloid type 1 (TRPV1) channel and ATP-sensitive channel P2X3 in the DRG. Immunohistochemistry of hindpaw muscles revealed damage to the muscle architecture and extensive infiltration of the tissue by cells of the myelomonocytic lineage 3 d after PEGPH20 injection. Peripheral macrophage ablation in macrophage Fas-induced apoptosis (MaFIA) mice, however, did not prevent the decreased voluntary activity and instead caused even lower levels of running. These results suggest that disruption of hyaluronic acid (HA) within the muscle extracellular matrix (ECM) sensitizes chemo-nociceptive muscle afferents possibly leading to altered pain-like behaviors. Ablation experiments suggest macrophages are necessary for adequate recovery of voluntary activity after HA disruption. These data support a role for HA and macrophages in tissue integrity and muscle pain development in patients taking PEGPH20.

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Mechanisms underlying immobilization‐induced muscle pain in rats

Cited by 13 publications

References 47 publications

Responses of cutaneous C-fiber afferents and spinal microglia after hindlimb cast immobilization in rats

Responses of cutaneous C-fiber afferents and spinal microglia after hindlimb cast immobilization in rats

Effect of belt electrode-skeletal muscle electrical stimulation on immobilization-induced muscle fibrosis

Disruption of hyaluronic acid in skeletal muscle induces decreased voluntary activity via chemosensitive muscle afferent sensitization in male mice

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