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Orofacial Pain: Molecular Mechanisms, Diagnosis and Treatment

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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 February 2020) | Viewed by 25063

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Special Issue Editors

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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Prof. Dr. Koichi Iwata

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Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan
Interests: pain; non-neuronal cells; trigeminal; neuroscience; animal research
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Dr. Shaista Afroz

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Aligarh Muslim University, India
Interests: satelite glia cell; cytokine

Special Issue Information

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. Yoshizo Matsuka
Prof. Koichi Iwata
Dr. Shaista Afroz
Guest Editors

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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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Research

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21 pages, 2965 KiB

Open AccessArticle

Role of CGRP in Neuroimmune Interaction via NF-κB Signaling Genes in Glial Cells of Trigeminal Ganglia

by Shaista Afroz, Rieko Arakaki, Takuma Iwasa, Arief Waskitho, Masamitsu Oshima and Yoshizo Matsuka

Int. J. Mol. Sci. 2020, 21(17), 6005; https://doi.org/10.3390/ijms21176005 - 20 Aug 2020

Cited by 4 | Viewed by 2626

Abstract

Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of Egr1, Myd88 and Akt1 and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway. Full article

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

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16 pages, 3151 KiB

Open AccessArticle

A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice

by Hui Shu, Sufang Liu, Yuanyuan Tang, Brian L. Schmidt, John C. Dolan, Larry L. Bellinger, Phillip R. Kramer, Steven D. Bender and Feng Tao

Int. J. Mol. Sci. 2020, 21(11), 4049; https://doi.org/10.3390/ijms21114049 - 5 Jun 2020

Cited by 14 | Viewed by 3243

Abstract

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity. Full article

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

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20 pages, 3050 KiB

Open AccessArticle

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

by Timea Aczél, Angéla Kecskés, József Kun, Kálmán Szenthe, Ferenc Bánáti, Susan Szathmary, Róbert Herczeg, Péter Urbán, Attila Gyenesei, Balázs Gaszner, Zsuzsanna Helyes and Kata Bölcskei

Int. J. Mol. Sci. 2020, 21(8), 2938; https://doi.org/10.3390/ijms21082938 - 22 Apr 2020

Cited by 16 | Viewed by 3398

Abstract

A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund’s adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4^-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4^-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4^-/^- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4^-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system. Full article

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

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15 pages, 1538 KiB

Open AccessArticle

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury

by Hiroharu Maegawa, Nayuka Usami, Chiho Kudo, Hiroshi Hanamoto and Hitoshi Niwa

Int. J. Mol. Sci. 2020, 21(6), 1945; https://doi.org/10.3390/ijms21061945 - 12 Mar 2020

Cited by 7 | Viewed by 2501

Abstract

While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABA_A) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain. Full article

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

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14 pages, 4552 KiB

Open AccessArticle

Involvement of Satellite Cell Activation via Nitric Oxide Signaling in Ectopic Orofacial Hypersensitivity

by Jun Lee, Kinuyo Ohara, Masamichi Shinoda, Yoshinori Hayashi, Asako Kubo, Shiori Sugawara, Sayaka Asano, Kumi Soma, Kohei Kanno, Masatoshi Ando, Ryo Koyama, Yuki Kimura, Kousuke Sakanashi, Toshimitsu Iinuma and Koichi Iwata

Int. J. Mol. Sci. 2020, 21(4), 1252; https://doi.org/10.3390/ijms21041252 - 13 Feb 2020

Cited by 4 | Viewed by 2692

Abstract

The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury. Full article

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

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16 pages, 4337 KiB

Open AccessArticle

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

by Shiori Sugawara, Masamichi Shinoda, Yoshinori Hayashi, Hiroto Saito, Sayaka Asano, Asako Kubo, Ikuko Shibuta, Akihiko Furukawa, Akira Toyofuku and Koichi Iwata

Int. J. Mol. Sci. 2019, 20(24), 6360; https://doi.org/10.3390/ijms20246360 - 17 Dec 2019

Cited by 22 | Viewed by 3947

Abstract

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin. Full article

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

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Review

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45 pages, 858 KiB

Open AccessReview

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

by Mohammad Zakir Hossain, Hiroshi Ando, Shumpei Unno and Junichi Kitagawa

Int. J. Mol. Sci. 2020, 21(4), 1423; https://doi.org/10.3390/ijms21041423 - 20 Feb 2020

Cited by 35 | Viewed by 5935

Abstract

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP. Full article

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

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