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Update on Molecular Mechanisms and Potential Drug Targets in Chronic...
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Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain

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

Deadline for manuscript submissions: closed (20 February 2022) | Viewed by 22186

Special Issue Editor

Prof. Dr. Ellen Niederberger

E-Mail Website
Guest Editor
Klinikum und Fachbereich Medizin Johann Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany
Interests: mechanisms of pain and inflammation; novel therapeutic drug targets
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

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 a decrease in patients’ quality of life and several comorbidities. 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 causes of pain development include a panel of molecular mechanisms comprising modifications of ion channels, receptor proteins, kinases, transcription factors, etc. The mechanisms comprise acute and long-term responses in the respective target proteins, but also epigenetic changes which are acquired over a patient’s lifetime as a result of environmental influences. They affect multiple tissues and cell types and may provide novel targets for potential pain therapies.

This Special Issue will gather new information on molecular mechanisms of pain and will therefore make a contribution towards the development of novel analgesics.

We look forward to your manuscript submissions.

Prof. Dr. Ellen Niederberger
Guest Editor

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Keywords

  • inflammation
  • neuropathy
  • hypersensitivity
  • microRNA
  • DNA methylation
  • histone methylation/acetylation
  • microglia
  • neurons

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Published Papers (5 papers)

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Research

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17 pages, 2830 KiB  
Article
The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain
by Moritz Möller, Christine V. Möser, Ulrike Weiß and Ellen Niederberger
Cells 2022, 11(12), 1967; https://doi.org/10.3390/cells11121967 - 19 Jun 2022
Cited by 4 | Viewed by 2551
Abstract
(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson’s disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the [...] Read more.
(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson’s disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the interconnection of αSyn and pain has not been clarified so far. (2) We investigated the potential effects of a αSyn knock-out on the nociceptive behaviour in mouse models of acute, inflammatory and neuropathic pain. Furthermore, we assessed the impact of αSyn deletion on pain-related cellular and molecular mechanisms in the spinal cord in these models. (3) Our results showed a reduction of acute cold nociception in αSyn knock-out mice while responses to acute heat and mechanical noxious stimulation were similar in wild type and knock-out mice. Inflammatory nociception was not affected by αSyn knock-out which is also mirrored by unaltered inflammatory gene expression. In contrast, in the SNI model of neuropathic pain, αSyn knock-out mice showed decreased mechanical allodynia as compared to wild type mice. This effect was associated with reduced proinflammatory mechanisms and suppressed activation of MAP kinase signalling in the spinal cord while endogenous antinociceptive mechanisms are not inhibited. (4) Our data indicate that αSyn plays a role in neuropathy and its inhibition might be useful to ameliorate pain symptoms after nerve injury. Full article
(This article belongs to the Special Issue Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain)
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18 pages, 2428 KiB  
Article
Slack Potassium Channels Modulate TRPA1-Mediated Nociception in Sensory Neurons
by Fangyuan Zhou, Katharina Metzner, Patrick Engel, Annika Balzulat, Marco Sisignano, Peter Ruth, Robert Lukowski, Achim Schmidtko and Ruirui Lu
Cells 2022, 11(10), 1693; https://doi.org/10.3390/cells11101693 - 19 May 2022
Cited by 4 | Viewed by 2716
Abstract
The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain [...] Read more.
The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) in sensory neurons. Mice lacking Slack globally (Slack−/−) or conditionally in sensory neurons (SNS-Slack−/−) demonstrated increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. By contrast, pain behavior induced by the TRP vanilloid 1 (TRPV1) activator capsaicin was normal in Slack-deficient mice. Patch-clamp recordings in sensory neurons and in a HEK cell line transfected with TRPA1 and Slack revealed that Slack-dependent potassium currents (IKS) are modulated in a TRPA1-dependent manner. Taken together, our findings highlight Slack as a modulator of TRPA1-mediated, but not TRPV1-mediated, activation of sensory neurons. Full article
(This article belongs to the Special Issue Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain)
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Review

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17 pages, 1253 KiB  
Review
The Scaffold Protein PICK1 as a Target in Chronic Pain
by Andreas Toft Sørensen, Joscha Rombach, Ulrik Gether and Kenneth Lindegaard Madsen
Cells 2022, 11(8), 1255; https://doi.org/10.3390/cells11081255 - 7 Apr 2022
Cited by 10 | Viewed by 3910
Abstract
Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, [...] Read more.
Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication. Full article
(This article belongs to the Special Issue Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain)
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19 pages, 997 KiB  
Review
A New Gal in Town: A Systematic Review of the Role of Galanin and Its Receptors in Experimental Pain
by Diana Fonseca-Rodrigues, Armando Almeida and Filipa Pinto-Ribeiro
Cells 2022, 11(5), 839; https://doi.org/10.3390/cells11050839 - 1 Mar 2022
Cited by 9 | Viewed by 3892
Abstract
Galanin is a neuropeptide expressed in a small percentage of sensory neurons of the dorsal root ganglia and the superficial lamina of the dorsal horn of the spinal cord. In this work, we systematically reviewed the literature regarding the role of galanin and [...] Read more.
Galanin is a neuropeptide expressed in a small percentage of sensory neurons of the dorsal root ganglia and the superficial lamina of the dorsal horn of the spinal cord. In this work, we systematically reviewed the literature regarding the role of galanin and its receptors in nociception at the spinal and supraspinal levels, as well as in chronic pain conditions. The literature search was performed in PubMed, Web of Science, Scopus, ScienceDirect, OVID, TRIP, and EMBASE using “Galanin” AND “pain” as keywords. Of the 1379 papers that were retrieved in the initial search, we included a total of 141 papers in this review. Using the ARRIVE guidelines, we verified that 89.1% of the works were of good or moderate quality. Galanin shows a differential role in pain, depending on the pain state, site of action, and concentration. Under normal settings, galanin can modulate nociceptive processing through both a pro- and anti-nociceptive action, in a dose-dependent manner. This peptide also plays a key role in chronic pain conditions and its antinociceptive action at both a spinal and supraspinal level is enhanced, reducing animals’ hypersensitivity to both mechanical and thermal stimulation. Our results highlight galanin and its receptors as potential therapeutic targets in pain conditions. Full article
(This article belongs to the Special Issue Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain)
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19 pages, 1885 KiB  
Review
Proton-Sensing GPCRs in Health and Disease
by Marco Sisignano, Michael J. M. Fischer and Gerd Geisslinger
Cells 2021, 10(8), 2050; https://doi.org/10.3390/cells10082050 - 10 Aug 2021
Cited by 36 | Viewed by 8331
Abstract
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the [...] Read more.
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies. Full article
(This article belongs to the Special Issue Update on Molecular Mechanisms and Potential Drug Targets in Chronic Pain)
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