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The Role of P2X Receptors in Nociception, Pain and Neuronal Toxicity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 9835

Special Issue Editor

Dr. Ralf Hausmann

E-Mail Website
Guest Editor
Institute of Clinical Pharmacology, RWTH Aachen University, Aachen, Germany
Interests: biophysics and molecular dynamics of gating and ion conduction in P2X receptors (P2XR); biophysical effects of pain-associated mutations in voltage-gated sodium channels (NaV); drug screening at P2XR and NaV

Special Issue Information

Dear Colleagues,

Extracellular ATP is an important co-transmitter and neuromodulator in numerous physiological and pathological processes. The targets of extracellular ATP are the nucleotide-activated P2 receptors that can be divided into ionotropic P2X receptors and metabotropic P2Y receptors. Strong evidence suggests that P2X receptors play important roles in sensory transmission and nociception as well as pain. Particularly well established is the crucial role of P2X3- and P2X2/3 receptors in primary sensory neurons or P2X4 receptors in the dorsal horn of the spinal cord in neuropathic and chronic inflammatory pain. P2X7 receptors play an important, but not entirely understood, role in chronic pain.

Some molecular mechanisms via which P2X receptors are involved in the detection and transmission of potentially painful stimuli or modulate nociception and pain have been uncovered, and mediators and signaling molecules involved have been identified. However, major receptor-specific molecular changes or differences in signaling pathways between acute and various chronic forms of pain remain unclear.

Furthermore, P2X receptors are involved in neuronal toxicity. For instance, the P2X7 receptor seems to amplify CNS damage in neurodegenerative diseases. However, the molecular mechanisms of neuronal and glial P2X receptor-mediated toxicity remain largely elusive, even though their overexpression in pathological states seems to be of importance.  

The aim and scope of this Special Issue is to present recent research findings or reviews that provide molecular insights into the role of P2X receptors in nociception, pain, and neuronal toxicity, in addition to the underlying molecular mechanisms and signaling pathways.

Dr. Ralf Hausmann
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • P2X receptors
  • Nociception and pain
  • Neuropathic and chronic inflammatory pain
  • Neuronal damage and toxicity
  • Sensory neurotransmission
  • Signaling pathways
  • Mediators, neurotransmitters and signaling molecules
  • Neuromodulation
  • P2X receptor antagonists
  • Molecular pharmacology

Published Papers (3 papers)

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Research

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21 pages, 3878 KiB  
Article
Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro
by Anna-Katharina Holzer, Ilinca Suciu, Christiaan Karreman, Thomas Goj and Marcel Leist
Int. J. Mol. Sci. 2022, 23(7), 3734; https://doi.org/10.3390/ijms23073734 - 29 Mar 2022
Cited by 8 | Viewed by 2623
Abstract
Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the [...] Read more.
Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca2+-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50–200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons. Full article
(This article belongs to the Special Issue The Role of P2X Receptors in Nociception, Pain and Neuronal Toxicity)
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20 pages, 3331 KiB  
Article
Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice
by Karin N. Westlund, Marena A. Montera, Aleyah E. Goins, Sascha R. A. Alles, Nikita Suri, Sabrina L. McIlwrath, Robyn Bartel, Ravi V. Durvasula and Adinarayana Kunamneni
Int. J. Mol. Sci. 2021, 22(24), 13612; https://doi.org/10.3390/ijms222413612 - 19 Dec 2021
Cited by 5 | Viewed by 3120
Abstract
Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, [...] Read more.
Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain. Full article
(This article belongs to the Special Issue The Role of P2X Receptors in Nociception, Pain and Neuronal Toxicity)
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Review

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15 pages, 1377 KiB  
Review
Platelets and the Role of P2X Receptors in Nociception, Pain, Neuronal Toxicity and Thromboinflammation
by Elias Rawish and Harald F. Langer
Int. J. Mol. Sci. 2022, 23(12), 6585; https://doi.org/10.3390/ijms23126585 - 13 Jun 2022
Cited by 9 | Viewed by 3288
Abstract
P2X receptors belong to a family of cation channel proteins, which respond to extracellular adenosine 5′-triphosphate (ATP). These receptors have gained increasing attention in basic and translational research, as they are central to a variety of important pathophysiological processes such as the modulation [...] Read more.
P2X receptors belong to a family of cation channel proteins, which respond to extracellular adenosine 5′-triphosphate (ATP). These receptors have gained increasing attention in basic and translational research, as they are central to a variety of important pathophysiological processes such as the modulation of cardiovascular physiology, mediation of nociception, platelet and macrophage activation, or neuronal–glial integration. While P2X1 receptor activation is long known to drive platelet aggregation, P2X7 receptor antagonists have recently been reported to inhibit platelet activation. Considering the role of both P2X receptors and platelet-mediated inflammation in neuronal diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and stroke, targeting purinergic receptors may provide a valuable novel therapeutic approach in these diseases. Therefore, the present review illuminates the role of platelets and purinergic signaling in these neurological conditions to evaluate potential translational implications. Full article
(This article belongs to the Special Issue The Role of P2X Receptors in Nociception, Pain and Neuronal Toxicity)
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