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Molecular Research in Orofacial Pain and Headache
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Molecular Research in Orofacial Pain and Headache

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 October 2026 | Viewed by 703

Special Issue Editor

Prof. Dr. Adriana Elena Bulboaca

E-Mail Website
Guest Editor
Pathophysiology Discipline, Morfofunctional Sciences Department, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Visctor Babes Str., Nr. 8, 400347 Cluj-Napoca, Romania
Interests: oxidative stress; neuroinflammation; pain pathophysiology; migraine; neurodegeneration; neuroplasticity; neuro-ophthalmology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Orofacial pain is a widespread health concern that significantly hinders an individual’s capacity to engage in daily activities. This type of pain can be classified into three main categories: nociceptive, neuropathic, and nociplastic pain. Each category involves different mechanisms and requires specific treatment approaches. For optimal treatment of orofacial pain disorders, a multidisciplinary pain management approach is essential. This approach should integrate both nonpharmacological and pharmacological modalities to address the diverse underlying causes and manifestations of pain. In this review, we focus on the current evidence and advancements in the pharmacological management of chronic orofacial pain: we explore the effectiveness of different medications, their mechanisms of action, and their role within a comprehensive pain management plan.

Orofacial pain is pain in the face, mouth, jaw, or neck, resulting from a wide range of conditions, including dental problems, temporomandibular joint (TMJ) disorders, and nerve issues like trigeminal neuralgia or headache. Causes can also include bruxism, and trauma, and it can be acute or chronic. Diagnosis often requires a specialist, and treatment is personalized, potentially including medications, physical therapy, splints, or a combination of approaches.

We invite researchers in this field to contribute to this Special Issue with studies that elucidate the main molecular mechanisms of orofacial pain and various types of headache, the signaling pathways and to identify specific targets and key molecules and potential therapeutic strategies.

Prof. Dr. Adriana Elena Bulboaca
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. 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

  • neuropathic pain
  • trigeminal neuralgia
  • temporomandibular joint disorders
  • headache
  • migraine
  • neuroplasticity

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Published Papers (2 papers)

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Research

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20 pages, 2309 KB  
Article
Electrophysiological Properties and Mechanical Sensitivity of Trigeminal Ganglionic Neurons That Innervate the Maxillary Sinus in Mice
by Saurav Gupta, Amit Raj Sharma, Jennifer Ling, Frederick Godley and Jianguo Gu
Int. J. Mol. Sci. 2026, 27(6), 2565; https://doi.org/10.3390/ijms27062565 - 11 Mar 2026
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Abstract
The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory [...] Read more.
The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (maxillary sinus TG neurons) were retrogradely labeled with the fluorescent dye DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Maxillary sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, maxillary sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of maxillary sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify maxillary sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders. Full article
(This article belongs to the Special Issue Molecular Research in Orofacial Pain and Headache)
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Review

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18 pages, 562 KB  
Review
The Role of Proinflammatory Cytokines in Temporomandibular Disorders: A Systematic Review
by Zuzanna Grzech-Leśniak, Agnieszka Matuszewska, Jakub Fiegler-Rudol, Marwan El Mobadder, Rafał Wiench and Mieszko Więckiewicz
Int. J. Mol. Sci. 2026, 27(8), 3677; https://doi.org/10.3390/ijms27083677 (registering DOI) - 20 Apr 2026
Abstract
Temporomandibular disorders (TMDs) are the prevalent causes of orofacial pain and dysfunction of the temporomandibular joint (TMJ) and masticatory muscles. Previous studies have revealed that proinflammatory cytokines play a key role in promoting inflammation, pain, and degeneration within the TMJ. In this context, [...] Read more.
Temporomandibular disorders (TMDs) are the prevalent causes of orofacial pain and dysfunction of the temporomandibular joint (TMJ) and masticatory muscles. Previous studies have revealed that proinflammatory cytokines play a key role in promoting inflammation, pain, and degeneration within the TMJ. In this context, the present systematic review synthesizes current evidence on various cytokines involved in the pathophysiology of TMDs and evaluates their associations with clinical signs and structural TMJ damage. A PRISMA-guided search (PROSPERO: CRD420251163290) was conducted in PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library to identify human-based, in vivo, and in vitro studies (January 2014 to September 2025) that assessed the roles of proinflammatory cytokines in TMDs. The following data were extracted from the identified studies: cytokine profiles, sampling methods, clinical outcomes, and TMJ structural changes. Study quality and risk of bias were systematically evaluated. A total of 15 studies (clinical, animal, and mechanistic) were included in the review. Tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) consistently emerged as the major contributors to synovitis, cartilage degradation, nociceptive sensitization, and bone resorption. Human studies showed that high levels of TNF-α, IL-1β, and IL-6 and chemokines such as C-C motif chemokine ligand 2 (CCL2) and regulated on activation, normal T-cell expressed and secreted (RANTES) were associated with TMJ pain, restricted mandibular motion, crepitus, malocclusion, and erosive changes on imaging. An increased ratio of TNF to soluble TNF receptor in synovial fluid correlated with both pain and condylar damage, suggesting that loss of cytokine control contributes to progressive joint destruction. TMDs, particularly inflammatory and degenerative subtypes, are cytokine-driven pathologies rather than purely mechanical disorders. TNF-α, IL-1β, and IL-6 are the promising candidate biomarkers of local inflammation and structural joint pathology. Standardized longitudinal studies are required to validate cytokine-based diagnostics and develop anti-cytokine therapeutics. Full article
(This article belongs to the Special Issue Molecular Research in Orofacial Pain and Headache)
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