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Brain Sciences
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Cellular and Molecular Mechanisms of Neuropathic Pain
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Cellular and Molecular Mechanisms of Neuropathic Pain

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Sensory and Motor Neuroscience".

Deadline for manuscript submissions: 20 November 2026 | Viewed by 5427

Special Issue Editor

Prof. Dr. Al-Khrasani Mahmoud

E-Mail Website
Guest Editor
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Interests: in vitro and vivo opioid pharmacology; in vitro pharmacology and applied biochemistry (isolated organs, brain slices, calcium imaging)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuropathic pain is a significant condition that impairs individuals' ability to fulfill their professional responsibilities, negatively impacting societal economic well-being. It arises from damage and/or diseases affecting the somatosensory system at peripheral, central, or both levels, leading to various morphological and neurochemical changes in pain processing pathways. The neurochemical alterations associated with neuropathic pain involve an imbalance of neurotransmitters responsible for pain modulation, resulting in both inhibitory and excitatory patterns. These changes complicate the experience of pain and challenge the efficacy of traditional therapies.

In this Special Issue, we invite papers and reviews that explore the mechanisms underlying neuropathic pain, particularly research focused on restoring the balance between the excitatory and inhibitory systems involved in pain sensation. We also encourage contributions investigating novel therapeutic targets and innovative pharmacological approaches—whether natural or synthetic—that show promise for managing this complex condition.

Your research is crucial for enhancing our understanding of neuropathic pain and improving treatment options for affected individuals.

Prof. Dr. Al-Khrasani Mahmoud
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 250 words) can be sent to the Editorial Office for assessment.

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. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). 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

  • neuropathic pain
  • mechanisms
  • novel targets
  • natural drugs
  • novel synthetic and semi-synthetic drugs
  • monoclonal antibodies

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Published Papers (4 papers)

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Research

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23 pages, 2272 KB  
Article
Neuroinflammation-Modulating Properties Combining Glutathione, N-Acetylcysteine, and Uridine Monophosphate in a Formulation Supplement: An In Vitro Study
by Simone Mulè, Francesca Parini, Rebecca Galla and Francesca Uberti
Brain Sci. 2025, 15(12), 1340; https://doi.org/10.3390/brainsci15121340 - 16 Dec 2025
Cited by 1 | Viewed by 1923
Abstract
Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical [...] Read more.
Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical formulation, SUPERALA CARNITINE® (Pharma Suisse Laboratories SpA, Milan, Italy), containing Alpha-Lipoic Acid (ALA), with a novel formulation, called SUPERALA CARNITINE® Forte, where ALA and vitamin B6 were replaced by N-acetylcysteine (NAC), Glutathione (GSH), and Uridine monophosphate (UMP). Methods: An indirect gut–peripheral nerve axis was employed to simulate oral absorption, metabolism, and effect on nervous tissues using 3D in vitro models. Both formulations and their individual components were assessed for cytotoxicity and permeability in the gut model (Caco-2 cells in Transwell®) and, after gut metabolism, for antioxidant capacity, anti-inflammatory activity, and neuroprotective potential in the peripheral nerve model. Results: SUPERALA CARNITINE® Forte improved cell viability and favoured the maintenance of intestinal integrity, showing enhanced permeability, and significantly reduced oxidative stress (OS) and pro-inflammatory cytokines (TNF-α, IL-2) at the peripheral nervous system. In addition, it increased levels of neuronal markers (p75, MPZ, NRG1, ERβ) and decreased NaV1.7 and NaV1.8 activity, indicating greater neuroprotection and analgesic modulation than the ALA-based formula. Conclusions: The replacement of ALA and vitamin B6 with NAC, GSH, and UMP produced favorable responses in vitro on neuronal cells, supporting a hypothetical potential interest in this nutraceutical combination and justifying further future in vivo investigations. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neuropathic Pain)
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Review

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27 pages, 2486 KB  
Review
Targeting Sigma-1 and Sigma-2 Receptors in Neuropathic Pain: Pharmacology, Ligand Development, and Translational Progress
by Carlo Reale, Giuliana Costanzo, Lorella Pasquinucci and Carmela Parenti
Brain Sci. 2026, 16(4), 371; https://doi.org/10.3390/brainsci16040371 - 29 Mar 2026
Viewed by 1006
Abstract
Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse [...] Read more.
Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neuropathic Pain)
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Graphical abstract

27 pages, 663 KB  
Review
Centrally Acting Skeletal Muscle Relaxants Sharing Molecular Targets with Drugs for Neuropathic Pain Management
by Judit Mária Kirchlechner-Farkas, David Arpad Karadi, Imre Boldizsár, Jr., Nariman Essmat, Anna Rita Galambos, Zoltán Patrik Lincmajer, Sarah Kadhim Abbood, Kornél Király, Éva Szökő, Tamás Tábi and Mahmoud Al-Khrasani
Brain Sci. 2026, 16(1), 67; https://doi.org/10.3390/brainsci16010067 - 31 Dec 2025
Viewed by 1799
Abstract
Treatment of neuropathic pain (NP) remains a challenge in clinical practice because the current treatment approaches produce satisfactory pain alleviation in only 30% of patients. This necessitates developing novel drugs or repurposing existing medications intended to manage other diseases. When the repurposing intendance [...] Read more.
Treatment of neuropathic pain (NP) remains a challenge in clinical practice because the current treatment approaches produce satisfactory pain alleviation in only 30% of patients. This necessitates developing novel drugs or repurposing existing medications intended to manage other diseases. When the repurposing intendance is chosen, similarity in the pharmacological properties should be hosted by the candidate drugs. Herein, this review sheds light on the mechanisms of certain centrally acting skeletal muscle relaxants (CMRs), specifically tolperisone. So far, data indicate that tolperisone displays voltage-gated sodium channel (VGSC) blocking properties with modulatory effect on voltage-gated calcium channels (VGCCs). These properties have led to recent preclinical research initiatives testing tolperisone in NP, resulting in positive outcomes. Furthermore, the review highlights the currently available VGSC blockers and proposes a strategy based on combining them with VGCC blockers that have been proven for the treatment of NP. This proposal is supported by the fact that tolperisone, in combination with pregabalin, has recently been shown to acutely halt NP. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neuropathic Pain)
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Other

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36 pages, 4323 KB  
Systematic Review
A Systematic Review of Lifestyle Interventions for Neuropathy and Neuropathic Pain: Alcohol Consumption and Avoidance
by Michael Klowak, Ezra J. Bado, Aquilla Reid-John, Rumaysa Dawood, Candice Madakadze and Andrea K. Boggild
Brain Sci. 2026, 16(6), 551; https://doi.org/10.3390/brainsci16060551 - 22 May 2026
Viewed by 156
Abstract
Background: Neuropathy and neuropathic pain (NP) are globally prevalent, remain difficult to manage, and are often exacerbated by underlying lifestyle factors. Alcohol use, particularly in the context of chronic consumption or dependence, is a recognized contributor to peripheral nerve damage, yet its [...] Read more.
Background: Neuropathy and neuropathic pain (NP) are globally prevalent, remain difficult to manage, and are often exacerbated by underlying lifestyle factors. Alcohol use, particularly in the context of chronic consumption or dependence, is a recognized contributor to peripheral nerve damage, yet its association with neuropathy/NP has not been systematically evaluated. This systematic review synthesizes the current evidence on alcohol exposure, including quantity, frequency, and dependency, and its association with the incidence, prevalence, and severity of neuropathy/NP. Methods: This systematic review included observational studies assessing alcohol consumption patterns or dependence in relation to neuropathy/NP outcomes and was conducted in accordance with PRISMA guidelines. Exposure types were analyzed independently, and pooled odds ratios and relative risks were generated when sufficient data were available. The review was registered with PROSPERO number CRD42023484158. Results: Following de-duplication and exclusions, 76 studies were included, comprising cohort (n = 15), case–control (n = 12), and cross-sectional (n = 49) designs. While associations varied by study design and exposure category, alcohol dependence and consumption were more consistently linked with increased neuropathy incidence and severity, including electrophysiological evidence of compromised function. Notably, in studies examining alcohol cessation, abstinence was linked to clinical improvements in neuropathy/NP symptoms such as hypoesthesia and muscle weakness. While heterogeneity and risk of bias were present, largely due to the subjective classification of alcohol exposure and a lack of universally applied objective neuropathy measurement tools, multiple pooled estimates reached statistical significance. Conclusions: Evidence from observational studies supports an association between alcohol use, especially dependence, and the development and progression of neuropathy/NP, although causality remains unproven. Abstinence may offer therapeutic benefit, though further abstinence- and/or harm reduction-related interventional studies are required to clarify causality and guide low-cost, adjunctive strategies for alcohol-related neuropathy/NP. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neuropathic Pain)
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