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Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021

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

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 20916

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Prof. Dr. Yoshizo Matsuka

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Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan
Interests: orofacial pain; neuropathic pain; prosthodontics; cytokine; neurotransmitter; trigeminal ganglion; botulinum toxin; nonodontogenic toothache
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Dear Colleagues,

Orofacial pain, which can be odontogenic or non-odontogenic in origin, is one of the leading causes of morbidity worldwide, affecting almost 26% of the world’s population. Due to the involvement of important structures in the orofacial vicinity, it may impact the aesthetics, speech, feeding and overall psychosocial well-being of affected individuals. Orofacial pain may range from simple inflammatory pain like toothache, periodontal pain, and pain related to oral ulceration to more serious and difficult to manage entities like neuropathic pain due to oral cancer or chemotherapeutic agents, trigeminal neuralgia, glossopharyngeal neuralgia, headaches, temporomandibular disorders and burning mouth syndrome. Basic science research on orofacial pain is progressing with a common goal of exploring more molecular targets involved in pain mechanism, diagnosis and treatment.

With this Special Issue, we aim to present novel fundamental science research that contributes to better understanding of orofacial pain mechanisms, diagnosis and investigation, and intervention. We intend to involve the broader audience interested in orofacial pain research and to bring fundamental science researchers onto the same platform to bridge the gap between laboratory bench and clinical research.

Prof. Dr. Yoshizo Matsuka
Guest Editor

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Keywords

orofacial pain
basic pain mechanisms
peripheral pain mechanisms
central pain mechanisms
management methodology
trigeminal system

Published Papers (7 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

Orofacial Pain: Molecular Mechanisms, Diagnosis, and Treatment 2021

by Yoshizo Matsuka

Int. J. Mol. Sci. 2022, 23(9), 4826; https://doi.org/10.3390/ijms23094826 - 27 Apr 2022

Cited by 8 | Viewed by 3056

Abstract

The Special Issue “Orofacial Pain: Molecular Mechanisms, Diagnosis, and Treatment 2021” contains 6 articles published by 41 authors from different countries focusing on nucleus accumbens core GABAergic neurons, receptor-interacting serine/threonine-protein kinase 1, pannexin 1-mediated ATP signaling, ultra-low-frequency transcutaneous electrical nerve stimulation, and triamcinolone acetonide. The content covers several pain models, including neuropathic pain caused by peripheral nerve constriction or malpositioned dental implants, tongue cancer, myogenous temporomandibular dysfunction, and oral ulcerative mucositis. In addition, a review paper on trigeminal neuralgia is included. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

Research

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14 pages, 4548 KiB

Open AccessArticle

TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats

by Jo Young Son, Jin Sook Ju, Yu Mi Kim and Dong Kuk Ahn

Int. J. Mol. Sci. 2022, 23(1), 506; https://doi.org/10.3390/ijms23010506 - 03 Jan 2022

Cited by 2 | Viewed by 1774

Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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14 pages, 3365 KiB

Open AccessArticle

Analgesic Mechanisms of Steroid Ointment against Oral Ulcerative Mucositis in a Rat Model

by Mako Naniwa, Chihiro Nakatomi, Suzuro Hitomi, Kazunari Matsuda, Takuya Tabuchi, Daijiro Sugiyama, Sayaka Kubo, Yuichi Miyamura, Kenichi Yoshino, Sumio Akifusa and Kentaro Ono

Int. J. Mol. Sci. 2021, 22(22), 12600; https://doi.org/10.3390/ijms222212600 - 22 Nov 2021

Cited by 7 | Viewed by 2239

Abstract

Despite the long history of use of steroid ointments for oral mucositis, the analgesic mechanism has not been fully elucidated. In this study, we examined the effects of triamcinolone acetonide (Tmc) on oral ulcerative mucositis-induced pain in conscious rats by our proprietary assay system. Based on evaluations of the physical properties and retention periods in the oral mucosa of human volunteers and rats, we selected TRAFUL^® ointment as a long-lasting base. In oral ulcerative mucositis model rats, TRAFUL^® with Tmc suppressed cyclooxygenase-dependent inflammatory responses with upregulations of glucocorticoid receptor-induced anti-inflammatory genes and inhibited spontaneous nociceptive behavior. When an ointment with a shorter residual period was used, the effects of Tmc were not elicited or were induced to a lesser extent. Importantly, TRAFUL^® with Tmc also improved oral ulcerative mucositis-induced mechanical allodynia, which has been reported to be independent of cyclooxygenase. Ca²⁺ imaging in dissociated trigeminal ganglion neurons showed that long-term preincubation with Tmc inhibited the hypertonic stimulation-induced Ca²⁺ response. These results suggest that the representative steroid Tmc suppresses oral ulcerative mucositis-induced pain by general anti-inflammatory actions and inhibits mechanical sensitivity in peripheral nerves. For drug delivery, long-lasting ointments such as TRAFUL^® are needed to sufficiently induce the therapeutic effects. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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14 pages, 5000 KiB

Open AccessArticle

Pannexin 1-Mediated ATP Signaling in the Trigeminal Spinal Subnucleus Caudalis Is Involved in Tongue Cancer Pain

by Ryo Koyama, Koichi Iwata, Yoshinori Hayashi, Suzuro Hitomi, Ikuko Shibuta, Akihiko Furukawa, Sayaka Asano, Tadayoshi Kaneko, Yoshiyuki Yonehara and Masamichi Shinoda

Int. J. Mol. Sci. 2021, 22(21), 11404; https://doi.org/10.3390/ijms222111404 - 22 Oct 2021

Cited by 6 | Viewed by 2293

Abstract

Pain is one of the most severe concerns in tongue cancer patients. However, the underlying mechanisms of tongue cancer pain are not fully understood. We investigated the molecular mechanisms of tongue cancer-induced mechanical allodynia in the tongue by squamous cell carcinoma (SCC) inoculation in rats. The head-withdrawal threshold of mechanical stimulation (MHWT) to the tongue was reduced following SCC inoculation, which was inhibited by intracisternal administration of 10Panx, an inhibitory peptide for pannexin 1 (PANX1) channels. Immunohistochemical analyses revealed that the expression of PANX1 was upregulated in the trigeminal spinal subnucleus caudalis (Vc) following SCC inoculation. The majority of PANX1 immunofluorescence was merged with ionized calcium-binding adapter molecule 1 (Iba1) fluorescence and a part of it was merged with glial fibrillary acidic protein (GFAP) fluorescence. Spike frequencies of Vc nociceptive neurons to noxious mechanical stimulation were significantly enhanced in SCC-inoculated rats, which was suppressed by intracisternal 10Panx administration. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons increased significantly in the Vc after SCC inoculation, which was inhibited by intracisternal 10Panx administration. SCC inoculation-induced MHWT reduction and increased pERK-IR Vc neuron numbers were inhibited by P2X7 purinoceptor (P2X7R) antagonism. Conversely, these effects were observed in the presence of P2X7R agonist in SCC-inoculated rats with PANX1 inhibition. SCC inoculation-induced MHWT reduction was significantly recovered by intracisternal interleukin-1 receptor antagonist administration. These observations suggest that SCC inoculation causes PANX1 upregulation in Vc microglia and adenosine triphosphate released through PANX1 sensitizes nociceptive neurons in the Vc, resulting in tongue cancer pain. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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15 pages, 2987 KiB

Open AccessArticle

Ultra-Low Frequency Transcutaneous Electrical Nerve Stimulation on Pain Modulation in a Rat Model with Myogenous Temporomandibular Dysfunction

by Yueh-Ling Hsieh, Chen-Chia Yang and Nian-Pu Yang

Int. J. Mol. Sci. 2021, 22(18), 9906; https://doi.org/10.3390/ijms22189906 - 14 Sep 2021

Cited by 6 | Viewed by 1982

Abstract

Masticatory myofascial pain (MMP) is one of the most common causes of chronic orofacial pain in patients with temporomandibular disorders. To explore the antinociceptive effects of ultra-low frequency transcutaneous electrical nerve stimulation (ULF-TENS) on alterations of pain-related biochemicals, electrophysiology and jaw-opening movement in an animal model with MMP, a total of 40 rats were randomly and equally assigned to four groups; i.e., animals with MMP receiving either ULF-TENS or sham treatment, as well as those with sham-MMP receiving either ULF-TENS or sham treatment. MMP was induced by electrically stimulated repetitive tetanic contraction of masticatory muscle for 14 days. ULF-TENS was then performed at myofascial trigger points of masticatory muscles for seven days. Measurable outcomes included maximum jaw-opening distance, prevalence of endplate noise (EPN), and immunohistochemistry for substance P (SP) and μ-opiate receptors (MOR) in parabrachial nucleus and c-Fos in rostral ventromedial medulla. There were significant improvements in maximum jaw-opening distance and EPN prevalence after ULF-TENS in animals with MMP. ULF-TENS also significantly reduced SP overexpression, increased MOR expression in parabrachial nucleus, and increased c-Fos expression in rostral ventromedial medulla. ULF-TENS may represent a novel and applicable therapeutic approach for improvement of orofacial pain induced by MMP. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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18 pages, 3909 KiB

Open AccessArticle

Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury

by Jaisan Islam, Elina KC, Soochong Kim, Hyong Kyu Kim and Young Seok Park

Int. J. Mol. Sci. 2021, 22(16), 8421; https://doi.org/10.3390/ijms22168421 - 05 Aug 2021

Cited by 8 | Viewed by 2370

Abstract

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation “ON” and “OFF” conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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Review

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15 pages, 325 KiB

Open AccessReview

The Molecular Basis and Pathophysiology of Trigeminal Neuralgia

by QiLiang Chen, Dae Ik Yi, Josiah Nathan Joco Perez, Monica Liu, Steven D. Chang, Meredith J. Barad, Michael Lim and Xiang Qian

Int. J. Mol. Sci. 2022, 23(7), 3604; https://doi.org/10.3390/ijms23073604 - 25 Mar 2022

Cited by 20 | Viewed by 6374

Abstract

Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease. Full article

(This article belongs to the Special Issue Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment 2021)

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