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Special Issue "Molecular Mechanisms in Pain Signaling Pathways"

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A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: 30 November 2023 | Viewed by 3563

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Special Issue Editors

Dr. Boris Krylov

E-Mail Website
Guest Editor

Head of the Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 199034 Saint Petersburg, Russia
Interests: nociception; sensory neurons; Na,K-ATPase as a signal transducer; Nav1.8 sodium channels

Dr. Ke Ma

E-Mail Website
Guest Editor

Medicine School, Shanghai Jiaotong University, Shanghai 200240, China
Interests: neuropathic pain; sympathetic nerve; sodium channel; opioid tolerance; interventional treatment

Special Issue Information

Dear Colleagues,

The medicinal treatment of chronic pain of various etiologies requires the use of opiates and/or opioids, which evoke adverse side effects at the organismal level and are highly addictive. For this reason, the world is experiencing an opioid crisis, representing one of the worst public health crises in history. When pain as a sensation loses its informational and protective function and becomes chronic, this pathology can be corrected only by drug administration. Regretfully, there are no safe and effective analgesics that can replace opiates in the arsenal of clinical medicine.

А possible approach to help solve this challenging problem is to modulate the functional activity of ion channels encoding the nociceptive information. It is the high-frequency component of impulse firing that carries information about the pain sensation to the CNS. The desire to specifically eliminate this high-frequency impulse activity component of polymodal nociceptors, leaving the signals of other modalities intact, forces us to look for novel approaches to the creation of fundamentally new, effective, and safe drugs that can replace opiates and opioids in clinical practice.

Dr. Boris Krylov
Dr. Ke Ma
Guest Editors

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Keywords

nociception
impulse firing
ion channels
Na,K-ATPase as a signal transducer

Published Papers (4 papers)

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Research

Open AccessArticle

Analgesic Effect of the Lysine-Containing Short Peptide Is Due to Modulation of the Na_V1.8 Channel Activation Gating System

Viktor A. Mikhailenko

Vera B. Plakhova

Valentina A. Penniyaynen

Svetlana A. Podzorova

and

Boris V. Krylov

Life 2023, 13(9), 1800; https://doi.org/10.3390/life13091800 - 24 Aug 2023

Viewed by 328

Abstract

The present work continues our recent series of articles that aim to elucidate the ligand–receptor binding mechanism of short cationic peptides to the Na_V1.8 channel in the nociceptive neuron. The applied methodological approach has involved several methods: the patch-clamp experimental evaluation of the effective charge of the Na_V1.8 channel activation gating system, the organotypic tissue culture method, the formalin test, and theoretical conformational analysis. The lysine-containing short peptide Ac-KEKK-NH₂ has been shown to effectively modulate the Na_V1.8 channel activation gating system. As demonstrated by the organotypic tissue culture method, the studied short peptide does not trigger the downstream signaling cascades controlling neurite outgrowth and should not be expected to evoke adverse side effects. Conformational analysis of the Ac-KEKK-NH₂ molecule has revealed that the distances between the positively charged amino groups of the lysine side chains are equal to 11–12 Å. According to the previously suggested mechanism of ligand–receptor binding of short peptides to the Na_V1.8 channel molecule, Ac-KEKK-NH₂ should exhibit an analgesic effect, which has been confirmed by the formalin test. The data obtained unequivocally indicate that the studied lysine-containing short peptide is a promising candidate for the role of a novel analgesic medicinal substance. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Pain Signaling Pathways)

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Open AccessArticle

Role of the Rhamnosyl Residue of Ouabain in the Activation of the Na,K-ATPase Signaling Function

Ilya V. Rogachevskii

Dmitriy M. Samosvat

Valentina A. Penniyaynen

Vera B. Plakhova

Svetlana A. Podzorova

Ke Ma

Georgy G. Zegrya

and

Boris V. Krylov

Life 2023, 13(7), 1500; https://doi.org/10.3390/life13071500 - 02 Jul 2023

Viewed by 655

Abstract

The signaling or non-pumping Na,K-ATPase function was first observed by us in the nociceptive neuron; Na,K-ATPase transduced the signals from the opioid-like receptors to Na_V1.8 channels. This study elucidates the role of the rhamnosyl residue of ouabain in the activation of the Na,K-ATPase signaling function. The effects resulting from activation of Na,K-ATPase signaling by the Ca²⁺ chelate complex of ouabain (EO) are not manifested upon removal of the rhamnosyl residue, as demonstrated in viable cells by the highly sensitive patch-clamp and organotypic cell culture methods. Docking calculations show that the rhamnosyl residue is involved in five intermolecular hydrogen bonds with the Na,K-ATPase α1-subunit, which are fundamentally important for activation of the Na,K-ATPase signaling function upon EO binding. The main contribution to the energy of EO binding is provided by its steroid core, which forms a number of hydrogen bonds and hydrophobic interactions with Na,K-ATPase that stabilize the ligand–receptor complex. Another critically important role in EO binding is expected to be played by the chelated Ca²⁺ cation, which should switch on strong intermolecular ionic interactions between the EO molecule and two α1-Na,K-ATPase amino acid residues, Glu116 and Glu117. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Pain Signaling Pathways)

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Open AccessArticle

Clinical Biomarker of Sterile Inflammation, HMGB1, in Patients with Chronic Non-Specific Low Back Pain: A Pilot Cross-Sectional Study

Julita A. Teodorczyk-Injeyan

Heba Khella

and

H. Stephen Injeyan

Life 2023, 13(2), 468; https://doi.org/10.3390/life13020468 - 08 Feb 2023

Viewed by 992

Abstract

The present study explores whether the inflammatory biomarker of sterile inflammation, high mobility box 1 (HMGB1), contributes to the inflammatory/nociceptive pathophysiology that characterizes chronic non-specific low back pain (LBP). Patients with chronic LBP (N = 10, >3 pain score on a 11-point Visual Analogue Scale, VAS) and asymptomatic participants (N = 12) provided peripheral blood (PB) samples. The proportion of classical CD14++ monocytes within PB leukocytes was determined by flow cytometry. The plasma and extracellular HMGB1 levels in unstimulated adherent cell (AC) cultures were measured using specific immunoassays. HMGB1 localization in ACs was assessed by immunofluorescent staining. The relative gene expression levels of tumor necrosis factor α (TNFα), interleukin-1 beta (IL-1

β

) and HMGB1 were determined by quantitative polymerase chain reaction (qRT-PCR) in relation to the pain intensity (11-point VAS scores) in patients with LBP. The extracellular release of HMGB1 in the LBP patient AC cultures was significantly elevated (p = 0.001) and accompanied by its relocation into the cytoplasm from the nuclei. The number of CD14++ monocytes in the patients’ PB was significantly (p = 0.03) reduced, while the HMGB1 plasma levels remained comparable to those of the controls. The mRNA levels of TNFα, IL-1β and HMGB1 were overexpressed relative to the controls and those of HMGB1 and IL-1β were correlated with the VAS scores at a significant level (p = 0.01–0.03). The results suggest that HMGB1 may play an important role in the pathophysiology of chronic non-specific LBP. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Pain Signaling Pathways)

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Open AccessArticle

Role of Transient Receptor Potential Vanilloid 1 in Sonic Hedgehog-Dependent Taste Bud Differentiation

and

Life 2023, 13(1), 75; https://doi.org/10.3390/life13010075 - 27 Dec 2022

Viewed by 1039

Abstract

Taste bud cell differentiation is extremely important for taste sensation. Immature taste bud cells cannot function during taste perception transmission to the nerve. In this study, we investigated whether hedgehog signaling affected taste bud cell differentiation and whether transient receptor potential vanilloid 1 (TRPV1) played a key role in dry mouth. The induction of dry mouth due to salivary gland resection (SGR) was confirmed on the basis of reduced salivation and disrupted fungiform papillae. The expression of keratin 8 (K8) of taste bud cells, neurofilament (NF), sonic hedgehog (Shh), and glioma-associated oncogene homolog 1 (Gli1) around taste bud cells was downregulated; however, the expression of TRPV1, P2X purinoceptor 3 (P2X3), and hematopoietic stem cell factor (c-Kit) was upregulated at the NF ends in the dry mouth group. To investigate the effect of TRPV1 defect on dry mouth, we induced dry mouth in the TRPV-/- group. The K8, NF, and P2X3 expression patterns were the same in the TRPV1 wild-type and TRPV1-/- dry mouth groups. However, Shh and c-Kit expression decreased regardless of dry mouth in the case of TRPV1 deficiency. These results indicated that TRPV1 positively regulated proliferation during taste bud cell injury by blocking the Shh/Gli1 pathway. In addition, not only cell proliferation but also differentiation of taste bud cells could not be regulated under TRPV1-deficiency conditions. Thus, TRPV1 positively regulates taste bud cell innervation and differentiation; this finding could be valuable in the clinical treatment of dry mouth-related taste dysfunction. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Pain Signaling Pathways)

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