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Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 28714

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Special Issue Editors

Dr. Chih-Cheng Chen

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Guest Editor

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Interests: molecular and genetic control of pain and mechanotransduction

Dr. Hiroshi Ueda

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Guest Editor

Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
Interests: pain; mechanotransduction; neurology

Special Issue Information

Dear Colleagues,

Effective treatments for chronic pain remain an unmet medical need. Although there are several commercially available pain-killers, such as opioids, channel blockers, gabapentinoids, and nonsteroid antiinflammation drugs, pain controls are not always based on the right molecular targets and/or mechanism of action. Our understanding of the molecular and neurobiological basis of chronic pain is still incomplete. Accumulating evidence has shown that tissue acidosis, neuroinflammation, and oxidative stress might be the common risky factors to trigger and maintain the intractable chronic pain associated with fibromyalgia and peripheral neuropathy. Therefore, the Special Issue of Cells should improve our understanding in novel pain mechanisms and peripheral analgesic pathways by including researchers working not only with pain mechanisms associated with tissue acidosis, neuroinflammation, and nerve injury, but also with endogenous antinociceptive pathways in the peripheral nervous system.

Dr. Chih-Cheng Chen
Dr. Hiroshi Ueda
Guest Editors

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Keywords

fibromyalgia
neuropathic pain
acidosis
neuroinflammation

Published Papers (7 papers)

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Research

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15 pages, 2785 KiB

Open AccessArticle

ATF3-Expressing Large-Diameter Sensory Afferents at Acute Stage as Bio-Signatures of Persistent Pain Associated with Lumbar Radiculopathy

by Jiann-Her Lin, Yu-Wen Yu, Yu-Chia Chuang, Cheng-Han Lee and Chih-Cheng Chen

Cells 2021, 10(5), 992; https://doi.org/10.3390/cells10050992 - 23 Apr 2021

Cited by 3 | Viewed by 2506

Abstract

The mechanism of pain chronicity is largely unknown in lumbar radiculopathy (LR). The anatomical location of nerve injury is one of the important factors associated with pain chronicity of LR. Accumulating evidence has shown constriction distal to the dorsal root ganglion (DRG) caused more severe radiculopathy than constriction proximal to the DRG; thereby, the mechanism of pain chronicity in LR could be revealed by comparing the differences in pathological changes of DRGs between nerve constriction distal and proximal to the DRG. Here, we used 2 rat models of LR with nerve constriction distal or proximal to the DRG to probe how the different nerve injury sites could differentially affect pain chronicity and the pathological changes of DRG neuron subpopulations. As expected, rats with nerve constriction distal to the DRG showed more persistent pain behaviors than those with nerve constriction proximal to the DRG in 50% paw withdraw threshold, weight-bearing test, and acetone test. One day after the operation, distal and proximal nerve constriction showed differential pathological changes of DRG. The ratios of activating transcription factor3 (ATF3)-positive DRG neurons were significantly higher in rats with nerve constriction distal to DRG than those with nerve constriction proximal to DRG. In subpopulation analysis, the ratios of ATF3-immunoreactivity (IR) in neurofilament heavy chain (NFH)-positive DRG neurons significantly increased in distal nerve constriction compared to proximal nerve constriction; although, both distal and proximal nerve constriction presented increased ratios of ATF3-IR in calcitonin gene-related peptide (CGRP)-positive DRG neurons. Moreover, the nerve constriction proximal to DRG caused more hypoxia than did that distal to DRG. Together, ATF3 expression in NHF-positive DRG neurons at the acute stage is a potential bio-signature of persistent pain in rat models of LR. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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15 pages, 5367 KiB

Open AccessFeature PaperArticle

pH Mapping of Skeletal Muscle by Chemical Exchange Saturation Transfer (CEST) Imaging

by Yu-Wen Chen, Hong-Qing Liu, Qi-Xuan Wu, Yu-Han Huang, Yu-Ying Tung, Ming-Huang Lin, Chia-Huei Lin, Tsai-Chen Chen, Eugene C. Lin and Dennis W. Hwang

Cells 2020, 9(12), 2610; https://doi.org/10.3390/cells9122610 - 4 Dec 2020

Cited by 6 | Viewed by 3074

Abstract

Magnetic resonance imaging (MRI) is extensively used in clinical and basic biomedical research. However, MRI detection of pH changes still poses a technical challenge. Chemical exchange saturation transfer (CEST) imaging is a possible solution to this problem. Using saturation transfer, alterations in the exchange rates between the solute and water protons because of small pH changes can be detected with greater sensitivity. In this study, we examined a fatigued skeletal muscle model in electrically stimulated mice. The measured CEST signal ratio was between 1.96 ppm and 2.6 ppm in the z-spectrum, and this was associated with pH values based on the ratio between the creatine (Cr) and the phosphocreatine (PCr). The CEST results demonstrated a significant contrast change at the electrical stimulation site. Moreover, the pH value was observed to decrease from 7.23 to 7.15 within 20 h after electrical stimulation. This pH decrease was verified by ³¹P magnetic resonance spectroscopy and behavioral tests, which showed a consistent variation over time. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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19 pages, 3793 KiB

Open AccessArticle

An Index Combining Lost and Remaining Nerve Fibers Correlates with Pain Hypersensitivity in Mice

by Han-Hsiung Chi, Jye-Chang Lee, Chih-Cheng Chen, Shih-Kuo Chen and Chen-Tung Yen

Cells 2020, 9(11), 2414; https://doi.org/10.3390/cells9112414 - 4 Nov 2020

Cited by 2 | Viewed by 4513

Abstract

Multiple peripheral nerves are known to degenerate after nerve compression injury but the correlation between the extent of nerve alteration and pain severity remains unclear. Here, we used intravital two-photon fluorescence microscopy to longitudinally observe changes in cutaneous fibers in the hind paw of Nav1.8-Cre-tdTomato mice after chronic constriction injury (CCI). Results showed that the CCI led to variable loss of the skin nerve plexus and intraepidermal nerve fibers. The timing of Nav1.8 nerve fiber loss correlated with the development of mechanical hypersensitivity. We compared a scoring approach that assessed whole-paw nerve degeneration with an index that quantified changes in the nerve plexus and terminals in multiple small regions of interest (ROI) from intravital images of the third and fifth toe tips. We found that the number of surviving nerve fibers was not linearly correlated with mechanical hypersensitivity. On the contrary, at 14 days after CCI, the moderately injured mice showed greater mechanical hypersensitivity than the mildly or severely injured mice. This indicates that both surviving and injured nerves are required for evoked neuropathic pain. In addition, these two methods may have the estimative effect as diagnostic and prognostic biomarkers for the assessment of neuropathic pain. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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19 pages, 7658 KiB

Open AccessFeature PaperArticle

Deletion of Acid-Sensing Ion Channel 3 Relieves the Late Phase of Neuropathic Pain by Preventing Neuron Degeneration and Promoting Neuron Repair

by Chia-Chi Kung, Yi-Chu Huang, Ting-Yun Hung, Chih-Yu Teng, Tai-Ying Lee and Wei-Hsin Sun

Cells 2020, 9(11), 2355; https://doi.org/10.3390/cells9112355 - 26 Oct 2020

Cited by 6 | Viewed by 3546

Abstract

Neuropathic pain is one type of chronic pain that occurs as a result of a lesion or disease to the somatosensory nervous system. Chronic excessive inflammatory response after nerve injury may contribute to the maintenance of persistent pain. Although the role of inflammatory mediators and cytokines in mediating allodynia and hyperalgesia has been extensively studied, the detailed mechanisms of persistent pain or whether the interactions between neurons, glia and immune cells are essential for maintenance of the chronic state have not been completely elucidated. ASIC3, a voltage-insensitive, proton-gated cation channel, is the most essential pH sensor for pain perception. ASIC3 gene expression is increased in dorsal root ganglion neurons after inflammation and nerve injury and ASIC3 is involved in macrophage maturation. ASIC currents are increased after nerve injury. However, whether prolonged hyperalgesia induced by the nerve injury requires ASIC3 and whether ASIC3 regulates neurons, immune cells or glial cells to modulate neuropathic pain remains unknown. We established a model of chronic constriction injury of the sciatic nerve (CCI) in mice. CCI mice showed long-lasting mechanical allodynia and thermal hyperalgesia. CCI also caused long-term inflammation at the sciatic nerve and primary sensory neuron degeneration as well as increased satellite glial expression and ATF3 expression. ASIC3 deficiency shortened mechanical allodynia and attenuated thermal hyperalgesia. ASIC3 gene deletion shifted ATF3 expression from large to small neurons and altered the M1/M2 macrophage ratio, thereby preventing small neuron degeneration and relieved pain. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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16 pages, 2342 KiB

Open AccessArticle

Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice

by Hiroshi Ueda, Hiroyuki Neyama and Yosuke Matsushita

Cells 2020, 9(8), 1906; https://doi.org/10.3390/cells9081906 - 16 Aug 2020

Cited by 8 | Viewed by 3234

Abstract

Lysophosphatidic acid (LPA) signaling is known to play key roles in the initiation and maintenance of various chronic pain models. Here we examined whether LPA signaling is also involved in diabetes-induced abnormal pain behaviors. The high-fat diet (HFD) showing elevation of blood glucose levels and body weight caused thermal, mechanical hyperalgesia, hypersensitivity to 2000 or 250 Hz electrical-stimulation and hyposensitivity to 5 Hz stimulation to the paw in wild-type (WT) mice. These HFD-induced abnormal pain behaviors and body weight increase, but not elevated glucose levels were abolished in LPA₁^−/− and LPA₃^−/− mice. Repeated daily intrathecal (i.t.) treatments with LPA_1/3 antagonist AM966 reversed these abnormal pain behaviors. Similar abnormal pain behaviors and their blockade by daily AM966 (i.t.) or twice daily Ki16425, another LPA_1/3 antagonist was also observed in db/db mice which show high glucose levels and body weight. Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA₁^−/− and LPA₃^−/− mice. These results suggest that LPA₁ and LPA₃ play key roles in the development of both type I and type II diabetic neuropathic pain. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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Review

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18 pages, 683 KiB

Open AccessReview

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

by Ti-Yen Yeh, I-Wei Luo, Yu-Lin Hsieh, To-Jung Tseng, Hao Chiang and Sung-Tsang Hsieh

Cells 2020, 9(12), 2725; https://doi.org/10.3390/cells9122725 - 21 Dec 2020

Cited by 19 | Viewed by 4384

Abstract

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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15 pages, 3138 KiB

Open AccessReview

Neuropathic Itch

by James Meixiong, Xinzhong Dong and Hao-Jui Weng

Cells 2020, 9(10), 2263; https://doi.org/10.3390/cells9102263 - 9 Oct 2020

Cited by 8 | Viewed by 6673

Abstract

Neurologic insults as varied as inflammation, stroke, and fibromyalgia elicit neuropathic pain and itch. Noxious sensation results when aberrantly increased afferent signaling reaches percept-forming cortical neurons and can occur due to increased sensory signaling, decreased inhibitory signaling, or a combination of both processes. To treat these symptoms, detailed knowledge of sensory transmission, from innervated end organ to cortex, is required. Molecular, genetic, and behavioral dissection of itch in animals and patients has improved understanding of the receptors, cells, and circuits involved. In this review, we will discuss neuropathic itch with a focus on the itch-specific circuit. Full article

(This article belongs to the Special Issue Molecular and Neurobiological Basis of Pain Sensation Involved in Fibromyalgia and Peripheral Neuropathy)

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