Sensory hyperinnervation and increase in <scp>NGF</scp>, <scp>TRPV1</scp> and <scp>P2X<sub>3</sub></scp> expression in the epidermis following cast immobilization in rats

Sekino, Yuki; Nakano, Jiro; Hamaue, Yohei; Chuganji, Sayaka; Sakamoto, Juichi; Yoshimura, Tsuyoshi; Origuchi, Tomoki; Okita, Minoru

doi:10.1002/j.1532-2149.2013.00412.x

Cited by 22 publications

(24 citation statements)

References 67 publications

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“…We found that NGF level and peripheral nerve fiber density increased in the gastrocnemius muscle during cast immobilization. These results are similar to those in our previous study showing that NGF expression in the keratinocytes and peripheral nerve fibers increased in immobilized skin . We assume that the increase in NGF level and peripheral nerve fiber density are related to the mechanisms underlying immobilization‐induced muscle pain.…”

Section: Discussionsupporting

confidence: 92%

“…We found that the PPT of the gastrocnemius muscle in the IM group significantly decreased unilaterally at 2 weeks after immobilization, and this decrease continued up to 4 weeks after immobilization. This PPT change in the skeletal muscle was almost the same as that seen in the skin using von Frey filament during cast immobilization in previous studies . However, because we measured the PPT of the skeletal muscle using the Randall‐Selitto apparatus through the skin, skin hyperalgesia may have also contributed in the IM group.…”

Section: Discussionsupporting

confidence: 72%

“…Two weeks of cast immobilization induced superficial pain in the skin, which was exacerbated when the immobilization period was prolonged . The mechanisms underlying the immobilization‐induced pain are likely associated with upregulation of nerve growth factor (NGF) and increased density of peripheral nerve fibers in the skin …”

Section: Introductionmentioning

confidence: 99%

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Mechanisms underlying immobilization‐induced muscle pain in rats

Oga

Goto²,

Sakamoto

et al. 2020

Muscle and Nerve

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Introduction:We investigated the mechanisms underlying immobilization-induced muscle pain in rats. Methods:In rat skeletal muscle, pressure pain threshold (PPT) of the gastrocnemius muscle was measured, and nerve growth factor (NGF) level, peripheral nerve fiber density, macrophage number, and interleukin-1β (IL-1β) mRNA expression were examined. An NGF receptor inhibitor was injected intramuscularly to assess the relationship between PPT and NGF levels.Results: Immobilization resulted in a decrease in PPT and increases in NGF level, C-fiber density, M1 macrophage number, and IL-1β mRNA expression. Injection of NGF receptor inhibitor reversed the decrease in PPT.Discussion: NGF upregulation may be a major contributor to immobilization-induced muscle pain. The increases in C-fiber density, M1 macrophage number, and IL-1β mRNA expression may be related to immobilization-induced muscle pain. K E Y W O R D SC fiber, immobilization, M1 macrophage, muscle pain, NGF

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 72%

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Mechanisms underlying immobilization‐induced muscle pain in rats

Oga

Goto²,

Sakamoto

et al. 2020

Muscle and Nerve

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“…The percentage of single-labeled neurons over total neurons and that of double-labeled over classical neuronal markers (NF200, CGRP or IB4)-IR neurons were calculated from 4–5 sections obtained from the L 4 or L 5 DRG. The cross-sectional area of TRPV1-positive neurons in DRGs, as well as optical density (OD) of TRPV1 immunoreactivity in DRGs, SDHs, epidermal and dermis (the area 0–50 µm below the dermo-epidermal junction, method see [26]) were measured using the free NIH software ‘Image J’v1.46r.…”

Section: Methodsmentioning

confidence: 99%

Spatio-Temporal Expression and Functional Involvement of Transient Receptor Potential Vanilloid 1 in Diabetic Mechanical Allodynia in Rats

Cui

et al. 2014

PLoS ONE

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Diabetic neuropathic pain (DNP) is one of the most common clinical manifestations of diabetes mellitus (DM), which is characterized by prominent mechanical allodynia (DMA). However, the molecular mechanism underlying it has not fully been elucidated. In this study, we examined the spatio-temporal expression of a major nociceptive channel protein transient receptor potential vanilloid 1 (TRPV1) and analyzed its functional involvement by intrathecal (i.t.) application of TRPV1 antagonists in streptozocin (STZ)-induced DMA rat models. Western blot and immunofluorescent staining results showed that TRPV1 protein level was significantly increased in the soma of the dorsal root ganglion (DRG) neurons on 14 days after STZ treatment (DMA 14 d), whereas those in spinal cord and skin (mainly from the central and peripheral processes of DRG neurons) had already been enhanced on DMA 7 d to peak on DMA 14 d. qRT-PCR experiments confirmed that TRPV1 mRNA level was significantly up-regulated in the DRG on DMA 7 d, indicating a preceding translation of TRPV1 protein in the soma but preferential distribution of this protein to the processes under the DMA conditions. Cell counting assay based on double immunostaining suggested that increased TRPV1-immunoreactive neurons were likely to be small-sized and CGRP-ergic. Finally, single or multiple intrathecal applications of non-specific or specific TRPV1 antagonists, ruthenium red and capsazepine, at varying doses, effectively alleviated DMA, although the effect of the former was more prominent and long-lasting. These results collectively indicate that TRPV1 expression dynamically changes during the development of DMA and this protein may play important roles in mechanical nociception in DRG neurons, presumably through facilitating the release of CGRP.

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“…P2X3 and P2X2/P2X3 double knockout mice display reduced nocifensive responses to ATP and formalin injection, as well as bladder hyporeflexia (Cockayne et al, 2000(Cockayne et al, , 2005, and both dorsal root and nodose ganglia neurons lose sensitivity to the selective agonist α,β-methylene ATP (α,β-meATP; Zhong et al, 2001). P2X3 expression increases in rat models of inferior alveolar nerve injury (Eriksson, Bongenhielm, Kidd, Matthews, & Fried, 1998), complete Freund's adjuvant (CFA)-induced monoarthritis (Shinoda, Ozaki, Asai, Nagamine, & Sugiura, 2005), and cast immobilisation (Sekino et al, 2014). In rat models, the number of P2X3-positive small diameter L4 and L5 dorsal root ganglion neurons increases after chronic constriction of the sciatic nerve (Novakovic et al, 1999) but decreases following axotomy (Bradbury et al, 1998).…”

mentioning

confidence: 99%

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Richards

Gever

Ford

et al. 2019

British J Pharmacology

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Background and Purpose The P2X3 receptor is an ATP‐gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first‐in‐class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK‐7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK‐7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions. Experimental Approach Whole‐cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK‐7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation. Key Results MK‐7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration‐ and state‐dependency to wash‐on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash‐on rate (τ value) for MK‐7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK‐7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight‐bearing discomfort. Conclusions and Implications MK‐7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions.

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Sensory hyperinnervation and increase in NGF, TRPV1 and P2X₃ expression in the epidermis following cast immobilization in rats

Abstract: The time course of the increase in peripheral nerve fibres and in the expression of TRPV1 and P2X3 paralleled the development of hypersensitivity, which suggests that histological changes of the skin following cast immobilization may have some relation to the resulting hypersensitivity.

Cited by 22 publications

References 67 publications

Mechanisms underlying immobilization‐induced muscle pain in rats

Mechanisms underlying immobilization‐induced muscle pain in rats

Spatio-Temporal Expression and Functional Involvement of Transient Receptor Potential Vanilloid 1 in Diabetic Mechanical Allodynia in Rats

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

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Sensory hyperinnervation and increase in NGF, TRPV1 and P2X3 expression in the epidermis following cast immobilization in rats

Abstract: The time course of the increase in peripheral nerve fibres and in the expression of TRPV1 and P2X3 paralleled the development of hypersensitivity, which suggests that histological changes of the skin following cast immobilization may have some relation to the resulting hypersensitivity.

Cited by 22 publications

References 67 publications

Mechanisms underlying immobilization‐induced muscle pain in rats

Mechanisms underlying immobilization‐induced muscle pain in rats

Spatio-Temporal Expression and Functional Involvement of Transient Receptor Potential Vanilloid 1 in Diabetic Mechanical Allodynia in Rats

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

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Sensory hyperinnervation and increase in NGF, TRPV1 and P2X₃ expression in the epidermis following cast immobilization in rats