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5 pages, 191 KiB

Open AccessEditorial

Novel Insights into Molecular Mechanisms of Chronic Pain

by Ellen Niederberger

Cells 2020, 9(10), 2220; https://doi.org/10.3390/cells9102220 - 1 Oct 2020

Cited by 4 | Viewed by 2204

Abstract

Pain is the most frequent cause triggering patients to visit a physician. The worldwide incidence of chronic pain is in the range of 20% of adults, and chronic pain conditions are frequently associated with several comorbidities and a drastic decrease in patients’ quality [...] Read more.

Pain is the most frequent cause triggering patients to visit a physician. The worldwide incidence of chronic pain is in the range of 20% of adults, and chronic pain conditions are frequently associated with several comorbidities and a drastic decrease in patients’ quality of life. Although several approved analgesics are available, such therapy is often not satisfying due to insufficient efficacy and/or severe side effects. Therefore, novel strategies for the development of safe and highly efficacious pain killers are urgently needed. To reach this goal, it is necessary to clarify the causes and signal transduction cascades underlying the onset and progression of the different types of chronic pain. The papers in this Special Issue cover a wide variety of mechanisms involved in different pain types such as inflammatory, neuropathic or cancer pain. Therefore, the results summarized here might contribute to a better understanding of the mechanisms in chronic pain and thereby to the development of novel therapeutic strategies for pain patients. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

Research

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19 pages, 4127 KiB

Open AccessArticle

Deepening the Mechanisms of Visceral Pain Persistence: An Evaluation of the Gut-Spinal Cord Relationship

by Elena Lucarini, Carmen Parisio, Jacopo J. V. Branca, Cristina Segnani, Chiara Ippolito, Carolina Pellegrini, Luca Antonioli, Matteo Fornai, Laura Micheli, Alessandra Pacini, Nunzia Bernardini, Corrado Blandizzi, Carla Ghelardini and Lorenzo Di Cesare Mannelli

Cells 2020, 9(8), 1772; https://doi.org/10.3390/cells9081772 - 24 Jul 2020

Cited by 24 | Viewed by 4287

Abstract

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of [...] Read more.

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa, transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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16 pages, 3594 KiB

Open AccessArticle

Rab27a Contributes to the Processing of Inflammatory Pain in Mice

by Tilman Gross, Gesine Wack, Katharina M. J. Syhr, Tanya Tolmachova, Miguel C. Seabra, Gerd Geisslinger, Ellen Niederberger, Achim Schmidtko and Wiebke Kallenborn-Gerhardt

Cells 2020, 9(6), 1488; https://doi.org/10.3390/cells9061488 - 18 Jun 2020

Cited by 9 | Viewed by 3519

Abstract

Tissue injury and inflammation may result in chronic pain, a severe debilitating disease that is associated with great impairment of quality of life. An increasing body of evidence indicates that members of the Rab family of small GTPases contribute to pain processing; however, [...] Read more.

Tissue injury and inflammation may result in chronic pain, a severe debilitating disease that is associated with great impairment of quality of life. An increasing body of evidence indicates that members of the Rab family of small GTPases contribute to pain processing; however, their specific functions remain poorly understood. Here, we found using immunofluorescence staining and in situ hybridization that the small GTPase Rab27a is highly expressed in sensory neurons and in the superficial dorsal horn of the spinal cord of mice. Rab27a mutant mice, which carry a single-nucleotide missense mutation of Rab27a leading to the expression of a nonfunctional protein, show reduced mechanical hyperalgesia and spontaneous pain behavior in inflammatory pain models, while their responses to acute noxious mechanical and thermal stimuli is not affected. Our study uncovers a previously unrecognized function of Rab27a in the processing of persistent inflammatory pain in mice. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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21 pages, 3463 KiB

Open AccessArticle

Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain

by Hodaya Leibovich, Nahum Buzaglo, Shlomo Tsuriel, Liat Peretz, Yaki Caspi, Ben Katz, Shaya Lev, David Lichtstein and Alexander M. Binshtok

Cells 2020, 9(4), 1007; https://doi.org/10.3390/cells9041007 - 18 Apr 2020

Cited by 6 | Viewed by 3603

Abstract

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the [...] Read more.

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique—PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats’ paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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15 pages, 2719 KiB

Open AccessArticle

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

by David Romeo-Guitart and Caty Casas

Cells 2020, 9(4), 808; https://doi.org/10.3390/cells9040808 - 27 Mar 2020

Cited by 10 | Viewed by 3714

Abstract

Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have focused on finding new therapies to increase axonal regeneration or to alleviate painful conditions. Still only a [...] Read more.

Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have focused on finding new therapies to increase axonal regeneration or to alleviate painful conditions. Still only a few of them have targeted both phenomena. Incipient or aberrant sensory axon regeneration is related to abnormal unpleasant sensations, such as hyperalgesia or allodynia. We recently have discovered NeuroHeal, a combination of two repurposed drugs; Acamprosate and Ribavirin. NeuroHeal is a neuroprotective agent that also enhances motor axon regeneration after PNI. In this work, we investigated its effect on sensory fiber regeneration and PNI-induced painful sensations in a rat model of spare nerve injury and nerve crush. The follow up of the animals showed that NeuroHeal treatment reduced the signs of neuropathic pain in both models. Besides, the treatment favored sensory axon regeneration, as observed in dorsal root ganglion explants. Mechanistically, the effects observed in vivo may improve the resolution of cell-protective autophagy. Additionally, NeuroHeal treatment modulated the P2X4-BDNF-KCC2 axis, which is an essential driver of neuropathic pain. These data open a new therapeutic avenue based on autophagic modulation to foster endogenous regenerative mechanisms and reduce the appearance of neuropathic pain in PNI. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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18 pages, 5827 KiB

Open AccessArticle

Tumors Provoke Inflammation and Perineural Microlesions at Adjacent Peripheral Nerves

by Jennifer Cohnen, Lisa Kornstädt, Lisa Hahnefeld, Nerea Ferreiros, Sandra Pierre, Ulrike Koehl, Thomas Deller, Gerd Geisslinger and Klaus Scholich

Cells 2020, 9(2), 320; https://doi.org/10.3390/cells9020320 - 29 Jan 2020

Cited by 7 | Viewed by 3482

Abstract

Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in [...] Read more.

Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in proximity of the sciatic nerve. All three tumor types caused mechanical hypersensitivity, thermal hyposensitivity and neuronal damage. Surprisingly the onset of the hypersensitivity was independent of physical contact of the nerve with the tumors and did not depend on infiltration of cancer cells in the sciatic nerve. However, macrophages and dendritic cells appeared on the outside of the sciatic nerves with the onset of the hypersensitivity. At the same time point downregulation of perineural tight junction proteins was observed, which was later followed by the appearance of microlesions. Fitting to the changes in the epi-/perineurium, a dramatic decrease of triglycerides and acylcarnitines in the sciatic nerves as well as an altered localization and appearance of epineural adipocytes was seen. In summary, the data show an inflammation at the sciatic nerves as well as an increased perineural and epineural permeability. Thus, interventions aiming to suppress inflammatory processes at the sciatic nerve or preserving peri- and epineural integrity may present new approaches for the treatment of tumor-induced pain. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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24 pages, 2399 KiB

Open AccessArticle

Human and Mouse TRPA1 Are Heat and Cold Sensors Differentially Tuned by Voltage

by Viktor Sinica, Lucie Zimova, Kristyna Barvikova, Lucie Macikova, Ivan Barvik and Viktorie Vlachova

Cells 2020, 9(1), 57; https://doi.org/10.3390/cells9010057 - 24 Dec 2019

Cited by 26 | Viewed by 4511

Abstract

Transient receptor potential ankyrin 1 channel (TRPA1) serves as a key sensor for reactive electrophilic compounds across all species. Its sensitivity to temperature, however, differs among species, a variability that has been attributed to an evolutionary divergence. Mouse TRPA1 was implicated in noxious [...] Read more.

Transient receptor potential ankyrin 1 channel (TRPA1) serves as a key sensor for reactive electrophilic compounds across all species. Its sensitivity to temperature, however, differs among species, a variability that has been attributed to an evolutionary divergence. Mouse TRPA1 was implicated in noxious cold detection but was later also identified as one of the prime noxious heat sensors. Moreover, human TRPA1, originally considered to be temperature-insensitive, turned out to act as an intrinsic bidirectional thermosensor that is capable of sensing both cold and heat. Using electrophysiology and modeling, we compare the properties of human and mouse TRPA1, and we demonstrate that both orthologues are activated by heat, and their kinetically distinct components of voltage-dependent gating are differentially modulated by heat and cold. Furthermore, we show that both orthologues can be strongly activated by cold after the concurrent application of voltage and heat. We propose an allosteric mechanism that could account for the variability in TRPA1 temperature responsiveness. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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Review

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33 pages, 2197 KiB

Open AccessReview

Amyloid Proteins and Peripheral Neuropathy

by Mohammed M. H. Albariqi, Sjoukje Engelsman, Niels Eijkelkamp and Jo W. M. Höppener

Cells 2020, 9(6), 1553; https://doi.org/10.3390/cells9061553 - 26 Jun 2020

Cited by 13 | Viewed by 5690

Abstract

Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share [...] Read more.

Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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17 pages, 1224 KiB

Open AccessReview

Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain

by Tuoxin Cao, Jessica J. Matyas, Cynthia L. Renn, Alan I. Faden, Susan G. Dorsey and Junfang Wu

Cells 2020, 9(5), 1194; https://doi.org/10.3390/cells9051194 - 11 May 2020

Cited by 52 | Viewed by 7167

Abstract

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor [...] Read more.

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential. Full article

(This article belongs to the Special Issue Novel Insights into Molecular Mechanisms of Chronic Pain)

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