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Neurobiological Mechanisms of Orofacial Chronic Pain

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 (31 December 2021) | Viewed by 25454

Special Issue Editors

Department of Neural and Pain Sciences, School of Dentistry, Program in Neuroscience, Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA
Interests: ion channels; pain; electrophysiology; nociceptors; transient receptor potential ion channels, trigeminal ganglia
Special Issues, Collections and Topics in MDPI journals
Department of Oral & Maxillofacial Surgery, School of Dentistry, Programs in Integrated Biomedical Sciences & Translational Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Interests: somatosensation; in vivo calcium imaging; voltage sensing imaging; in vivo second messengers imaging; network activity of primary sensory neuron (dorsal root ganglia & trigeminal ganglia) and surrounding cells; electrophysiologic recording; chronic pain; chronic itch; signaling molecules for nociception

Special Issue Information

Dear colleagues,

Orofacial pain arises not only from skin and mucosa but also from deep tissues such as masticatory muscles and joints. A wide variety of etiologies, such as tissue inflammation and nerve injury, leads to chronic pain that is often resistant to conventional therapies. Multiple idiopathic chronic pain conditions in orofacial regions, such as temporomandibular joint disorders (TMD), burning mouth syndrome (BMS), or atypical odontalgia, are very difficult to diagnose and properly treat. In spite of great advances over the last few decades, the neurobiological mechanisms underlying chronic pain conditions of the orofacial area are still not clearly understood.

This Special Issue is devoted to better understanding the neurobiological mechanisms of orofacial pain. The scope includes but is not limited to peripheral and central mechanisms of orofacial pain, neural pathways or signaling mechanisms in sensory ganglia or brain, genetic and epigenetic mechanisms, and neural and synaptic plasticity in preclinical models. The Special Issue also welcomes translational studies and clinical studies involving human subjects or functional MRI associated with orofacial pain. A more detailed understanding of the unique neurobiology of orofacial pain should help us develop novel methods and therapeutics for better treating orofacial persistent pain.

Prof. Dr. Man-Kyo Chung
Dr. Yu Shin Kim
Guest Editors

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Keywords

  • orofacial pain
  • trigeminal system
  • neural circuit of orofacial neuropathy
  • chronic pain
  • preclinical study
  • human study

Published Papers (6 papers)

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Research

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18 pages, 4102 KiB  
Article
17β-Estradiol Exacerbated Experimental Occlusal Interference-Induced Chronic Masseter Hyperalgesia by Increasing the Neuronal Excitability and TRPV1 Function of Trigeminal Ganglion in Ovariectomized Rats
by Yun Liu, Xiao-Xiang Xu, Ye Cao, Si-Yi Mo, Shan-Shan Bai, Ying-Ying Fan, Xiao-Yu Zhang and Qiu-Fei Xie
Int. J. Mol. Sci. 2021, 22(13), 6945; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136945 - 28 Jun 2021
Cited by 8 | Viewed by 1877
Abstract
Pain symptoms in temporomandibular disorders (TMD) predominantly affect reproductive women, suggesting that estrogen regulates pain perception. However, how estrogen contributes to chronic TMD pain remains largely unclear. In the present study, we performed behavioral tests, electrophysiology, Western blot and immunofluorescence to investigate the [...] Read more.
Pain symptoms in temporomandibular disorders (TMD) predominantly affect reproductive women, suggesting that estrogen regulates pain perception. However, how estrogen contributes to chronic TMD pain remains largely unclear. In the present study, we performed behavioral tests, electrophysiology, Western blot and immunofluorescence to investigate the role and underlying mechanisms of estrogen in dental experimental occlusal interference (EOI)-induced chronic masseter mechanical hyperalgesia in rats. We found that long-term 17β-estradiol (E2) replacement exacerbated EOI-induced masseter hyperalgesia in a dose-dependent manner in ovariectomized (OVX) rats. Whole-cell patch-clamp recordings demonstrated that E2 (100 nM) treatment enhanced the excitability of isolated trigeminal ganglion (TG) neurons in OVX and OVX EOI rats, and EOI increased the functional expression of transient receptor potential vanilloid-1 (TRPV1). In addition, E2 replacement upregulated the protein expression of TRPV1 in EOI-treated OVX rats. Importantly, intraganglionic administration of the TRPV1 antagonist AMG-9810 strongly attenuated the facilitatory effect of E2 on EOI-induced masseter mechanical sensitivity. These results demonstrate that E2 exacerbated EOI-induced chronic masseter mechanical hyperalgesia by increasing TG neuronal excitability and TRPV1 function. Our study helps to elucidate the E2 actions in chronic myogenic TMD pain and may provide new therapeutic targets for relieving estrogen-sensitive pain. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
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16 pages, 5656 KiB  
Article
Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain
by Nuria García-Magro, Yasmina B. Martin, Pilar Negredo, Francisco Zafra and Carlos Avendaño
Int. J. Mol. Sci. 2021, 22(9), 4564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094564 - 27 Apr 2021
Cited by 3 | Viewed by 2322
Abstract
Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are [...] Read more.
Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of ‘patches’ of higher expression, interspersed within a less immunoreactive ‘matrix’, which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
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Review

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27 pages, 2684 KiB  
Review
Chronic Orofacial Pain: Models, Mechanisms, and Genetic and Related Environmental Influences
by Barry J. Sessle
Int. J. Mol. Sci. 2021, 22(13), 7112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137112 - 01 Jul 2021
Cited by 42 | Viewed by 4302
Abstract
Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to [...] Read more.
Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
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17 pages, 386 KiB  
Review
Potential Molecular Targets for Treating Neuropathic Orofacial Pain Based on Current Findings in Animal Models
by Yukinori Nagakura, Shogo Nagaoka and Takahiro Kurose
Int. J. Mol. Sci. 2021, 22(12), 6406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126406 - 15 Jun 2021
Cited by 9 | Viewed by 2716
Abstract
This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category [...] Read more.
This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
19 pages, 2053 KiB  
Review
Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment
by Man-Kyo Chung, Sheng Wang, Se-Lim Oh and Yu Shin Kim
Int. J. Mol. Sci. 2021, 22(11), 5810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115810 - 28 May 2021
Cited by 12 | Viewed by 9310
Abstract
The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, [...] Read more.
The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
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21 pages, 2006 KiB  
Review
Glia and Orofacial Pain: Progress and Future Directions
by Yi Ye, Elizabeth Salvo, Marcela Romero-Reyes, Simon Akerman, Emi Shimizu, Yoshifumi Kobayashi, Benoit Michot and Jennifer Gibbs
Int. J. Mol. Sci. 2021, 22(10), 5345; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105345 - 19 May 2021
Cited by 19 | Viewed by 3916
Abstract
Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion [...] Read more.
Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia–neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions. Full article
(This article belongs to the Special Issue Neurobiological Mechanisms of Orofacial Chronic Pain)
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