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New Insights into the Molecular Mechanisms of Chronic Pain

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 January 2025 | Viewed by 4008

Special Issue Editors


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Guest Editor
Departamento de Biomedicina–Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Interests: glial cells; dorsal root ganglia; descending pain modulation

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Guest Editor
Departamento de Biomedicina–Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Interests: descending pain modulation; opioids; diffuse noxious inhibitory controls (DNIC)

Special Issue Information

Dear Colleagues,

Chronic pain of various aetiologies affects a high percentage of the population worldwide and is responsible for high costs to society. It is associated with several comorbidities that negatively impact the quality of life of patients and their close relatives. Chronic pain is considered a disease on its own, but the available treatments are not always effective and present many side effects. Despite the progress made in the last few decades towards understanding chronic pain neurobiology, there is still a large gap regarding the role of many cell types, molecules and their receptors, and the molecular identity of all the pathways involved. In particular, the molecular characterization of the circuitries implicated in descending modulation as well as those related with the cognitive and affective dimensions of pain is still underexplored. Also relevant, but poorly investigated, are the differences between sexes in pain circuitries and how they affect chronic pain. In this Special Issue, we welcome all manuscripts bringing new insights into these topics.

Dr. Fani L. Neto
Dr. Isabel Martins
Guest Editors

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Keywords

  • dorsal root ganglia
  • spinal cord
  • brain
  • opioids
  • monoamines
  • GABA
  • anxiety
  • depression
  • cognition
  • optogenetics
  • electrophysiology
  • behavior
  • glial cells

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Published Papers (3 papers)

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Research

15 pages, 855 KiB  
Article
Genetic Influences of Proinflammatory Cytokines on Pain Severity in Patients with Temporomandibular Disorders
by Marko Zlendić, Ema Vrbanović Đuričić, Koraljka Gall Trošelj, Marko Tomljanović, Kristina Vuković Đerfi and Iva Z. Alajbeg
Int. J. Mol. Sci. 2024, 25(16), 8730; https://doi.org/10.3390/ijms25168730 - 10 Aug 2024
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Abstract
This case-control study investigated single nucleotide polymorphism (SNP) genotypes (CXC motif chemokine ligand 8 (CXCL8): rs2227306 and rs2227307 and tumor necrosis factor (TNF): rs1800629) in 85 patients with pain-related temporomandibular disorders (TMDp) and 85 controls to explore their associations [...] Read more.
This case-control study investigated single nucleotide polymorphism (SNP) genotypes (CXC motif chemokine ligand 8 (CXCL8): rs2227306 and rs2227307 and tumor necrosis factor (TNF): rs1800629) in 85 patients with pain-related temporomandibular disorders (TMDp) and 85 controls to explore their associations with TMDp presence, pain intensity (low/high), and the presence of chronic arthralgia/myalgia. TMDp was diagnosed using a validated protocol, and polymorphisms were genotyped from buccal mucosa swabs using TaqMan assays. High pain intensity individuals had an increased risk for carrying minor allele “G” (rs2227307) and “T” (rs2227306) compared to controls (76% vs. 55.3%, p = 0.012; 72% vs. 54.1%, p = 0.030, respectively). Carriers of the minor allele “G” (rs2227307) were more prevalent in TMDp patients with arthralgia compared to controls (70.30% vs. 55.30%, p = 0.037). According to logistic regression, the most important predictors for high pain intensity were minor allele “G” of rs2227307 (OR 2.435, 95% CI 1.123–5.282), increasing age (OR 1.038, 95% CI 1.002–1.075), and female sex (OR 4.592, 95% CI 1.289–16.361). The explored gene polymorphisms were not significant risk factors for TMDp presence. These findings highlight the importance of genetic variations, particularly rs2227307, in understanding the diverse clinical manifestations of temporomandibular disorders. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Chronic Pain)
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17 pages, 2507 KiB  
Article
Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases
by Kaalindi Misra, Milena Ślęczkowska, Silvia Santoro, Monique M. Gerrits, Elisabetta Mascia, Margherita Marchi, Erika Salvi, Hubert J. M. Smeets, Janneke G. J. Hoeijmakers, Filippo Giovanni Martinelli Boneschi, Massimo Filippi, Giuseppe Lauria Pinter, Catharina G. Faber and Federica Esposito
Int. J. Mol. Sci. 2024, 25(13), 7248; https://doi.org/10.3390/ijms25137248 - 30 Jun 2024
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Abstract
Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing [...] Read more.
Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the “Nicotinic acetylcholine receptor signaling pathway”. Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Chronic Pain)
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18 pages, 7236 KiB  
Article
MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study
by Shaojing Ye, Nilesh M. Agalave, Fei Ma, Dlovan F. D. Mahmood, Asma Al-Grety, Payam E. Khoonsari, Lin Leng, Camilla I. Svensson, Richard Bucala, Kim Kultima and Pedro L. Vera
Int. J. Mol. Sci. 2024, 25(8), 4484; https://doi.org/10.3390/ijms25084484 - 19 Apr 2024
Viewed by 1212
Abstract
Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no [...] Read more.
Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no bladder inflammation. Persistent BHA is mediated by spinal macrophage migration inhibitory factor (MIF), and is associated with changes in lumbosacral proteomics. We investigated the contribution of individual spinal MIF receptors to persistent bladder pain as well as the spinal proteomics changes associated with relief of persistent BHA by spinal MIF antagonism. Female mice with persistent BHA received either intrathecal (i.t.) MIF monoclonal antibodies (mAb) or mouse IgG1 (isotype control antibody). MIF antagonism temporarily reversed persistent BHA (peak effect: 2 h), while control IgG1 had no effect. Moreover, i.t. antagonism of the MIF receptors CD74 and C-X-C chemokine receptor type 4 (CXCR4) partially reversed persistent BHA. For proteomics experiments, four separate groups of mice received either repeated intravesical scrambled peptide and sham i.t. injection (control, no pain group) or repeated intravesical PAR4 and: sham i.t.; isotype IgG1 i.t. (15 μg); or MIF mAb (15 μg). L6-S1 spinal segments were excised 2 h post-injection and examined for proteomics changes using LC-MS/MS. Unbiased proteomics analysis identified and relatively quantified 6739 proteins. We selected proteins that showed significant changes compared to control (no pain group) after intravesical PAR4 (sham or IgG i.t. treatment) and showed no significant change after i.t. MIF antagonism. Six proteins decreased during persistent BHA (V-set transmembrane domain-containing protein 2-like confirmed by immunohistochemistry), while two proteins increased. Spinal MIF antagonism reversed protein changes. Therefore, spinal MIF and MIF receptors mediate persistent BHA and changes in specific spinal proteins. These novel MIF-modulated spinal proteins represent possible new targets to disrupt spinal mechanisms that mediate persistent bladder pain. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Chronic Pain)
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