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      Animal models in the study and treatment of orofacial pain

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          Abstract

          Background

          Pain is one of the first causes of medical consultation in the world and by extension of dental consultation too. Orofacial pain comprehends the oral and facial regions including teeth, oral mucosa, gingiva, tongue and lips, but also the muscles of the jaw and neck, the temporomandibular joint, face, head and neck. Despite its highly estimated prevalence, it appears controversial and hard to quantify given the lack of common criteria to select the population under study and the difficulties to classify the different types of pain. Although for many patients the problem eventually fades after tissue healing, certain sub-chronic and chronic pain conditions remain notoriously undertreated. In this respect, animal models can be of great help.

          Material and Methods

          A systematic search was conducted in PubMed-Medline with appropriate keywords: orofacial pain, prevalence and dentist. Seven groups were generated and a second search based on each of these groups and on animal models was made. Search was restricted to English and Spanish, but no time restriction was applied.

          Results

          There are as yet few experimental models of orofacial pain: there hardly exists no other than trigeminal nerve injury for neuropathic pain, a bunch of oral squamous cell carcinoma models (mainly referred to the tongue) for cancer pain and none for the painful swelling of salivary glands. Similarly occurs for the burning mouth syndrome. A few more exist for inflammatory odontalgiae, aphthae, joint, myofascial and muscle inflammatory pains, although scarcely diverse as regards the nature of the noxious stimulus.

          Conclusions

          Given the relevance of envisaging the mechanistic of the various types of orofacial pain, new experimental models are needed on the basis of the dentist’s perspective for their correct management.

          Key words:Orofacial pain, neuralgia, odontalgia, oral cancer, animal models.

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          Most cited references34

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          Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve.

          Video recordings of free behavior and responses to mechanical facial stimulation were analyzed to assess whether chronic constriction injury (CCI) to the rat's infraorbital nerve (IoN) results in behavioral alterations indicative of neuropathic pain. A unilateral CCI was produced by placing loose chromic gut ligatures around the IoN. After CCI to the IoN, rats exhibited changes in both non-evoked and evoked behavior. Behavioral changes developed in two phases. Early after CCI (postoperative days 1-15), rats showed increased face-grooming activity with face-wash strokes directed to the injured nerve territory, while the responsiveness to stimulation of this area was decreased. Later after CCI (postoperative days 15-130), the prevalence of asymmetric face grooming was reduced but remained significantly increased compared to control rats. The early hyporesponsiveness was abruptly replaced by an extreme hyperresponsiveness: all stimulus intensities applied to the injured nerve territory evoked the "maximal" response (brisk head withdrawal, avoidance behavior plus directed face grooming). This response was never observed in control rats. Concurrently, IoN ligation rats showed a limited increase in the responsiveness to stimulation of the contralateral IoN territory, and around postoperative days 30-40 the responsiveness to stimulation of facial areas outside the IoN territories also increased. The hyperresponsiveness to stimulation of the ligated IoN territory slightly decreased from 60 d postoperative. Throughout the study, IoN ligation rats showed decreased exploratory behavior, displayed more freezing-like behavior, had a slower body weight gain, and a higher defecation rate, compared to control rats. The behavioral alterations observed after CCI to the IoN are indicative of severe sensory disturbances within the territory of the injured nerve: mechanical allodynia develops after a period of relative hypo-/anesthesia during which behavioral signs of recurrent spontaneous, aversive (possibly painful) sensations (paresthesias/dysesthesias) are maximal.
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            Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve

            Background Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC) model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity. Results The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild nerve trauma. Nerve edema is observed in the contacting infraorbital nerve bundle as well as macrophage infiltration in the trigeminal ganglia. Centrally in the spinal trigeminal nucleus, increased immunoreactivity for an activated microglial marker is evident (OX42, postoperative day 70). Mechanical thresholds of the affected whisker pad are significantly decreased on day 3 after chromic gut suture placement, persisting at least 10 weeks. The mechanical allodynia is reversed by suppression of microglial activation. Cold allodynia was detected at 4 weeks. Conclusions A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2) is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.
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              Mechanical allodynia and thermal hyperalgesia induced by experimental squamous cell carcinoma of the lower gingiva in rats.

              We developed a rat model of oral cancer pain by inoculating cancer cells into the lower gingiva. A squamous cell carcinoma (SCC) derived from Fisher rats, SCC-158, was inoculated into the subperiosteal tissue on the lateral side of the lower gingiva in male Fisher rats. Inoculation of cancer cells induced marked mechanical allodynia and thermal hyperalgesia in the ipsilateral maxillary and mandibular nerve area. Infiltration of the tumor cells into the mandible and the completely encompassed inferior alveolar nerve was observed. Calcitonin gene-related peptide (CGRP)-, substance P (SP)-, ATP receptor (P2X(3))-, and capsaicin receptor (TRPV1)-immunoreactive cells strikingly increased in the small-cell group of trigeminal ganglia (TGs) after tumor cell inoculation. The TRPV1-immunoreactive cells also increased in the medium- and large-cell groups. Retrograde tracing combined with immunofluorescence techniques revealed the increased expression of peptides and the receptors in maxillary nerve afferent neurons. These results suggest that inoculation of SCC cells into the lower gingiva produces mechanical allodynia and thermal hyperalgesia, indicating the establishment of a novel rat model of oral cancer pain. Increased expression of CGRP, SP, P2X(3), and TRPV1 in the TG may be involved in the behavioral changes in this model. To clarify the mechanisms of oral cancer pain, we examined the expression of calcitonin gene-related peptide, substance P, ATP receptor P2X(3), and capsaicin receptor TRPV1 in trigeminal ganglia. Characterizations of these molecular systems which mediate pain perception are important to develop novel clinical tools for promoting relief of oral cancer pain.
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                Author and article information

                Journal
                J Clin Exp Dent
                J Clin Exp Dent
                Medicina Oral S.L.
                Journal of Clinical and Experimental Dentistry
                Medicina Oral S.L.
                1989-5488
                1 April 2019
                April 2019
                : 11
                : 4
                : e382-e390
                Affiliations
                [1 ]PhD, Visiting Professor. Area of Pharmacology, Nutrition and Bromatology. Department of Basic Health Sciences. School of Health Sciences. Universidad Rey Juan Carlos (URJC), Alcorcón, Madrid (Spain) – I+D+i Medicinal Chemistry Institute (IQM) associated unit, (CSIC)
                [2 ]DDS, PhD. Adjunct Professor. Area of Stomatology. Department of Medicine and Surgery, Psychology, Preventive Medicine and Public Health, Immunology and Medical Microbiology, Nursing and Stomatology. School of Health Sciences. Universidad Rey Juan Carlos (URJC), Alcorcón, Madrid, Spain
                [3 ]PhD, Professor. Area of Pharmacology, Nutrition and Bromatology. Department of Basic Health Sciences. School of Health Sciences. Universidad Rey Juan Carlos (URJC), Alcorcón, Madrid (Spain) – I+D+i Medicinal Chemistry Institute (IQM) associated unit, (CSIC)
                Author notes
                Area of Pharmacology, Nutrition & Bromatology Department of Basic Health Sciences School of Health Sciences Universidad Rey Juan Carlos (URJC) Avda. de Atenas, s/n 28922 Alcorcón, Madrid, Spain , E-mail: miguelangel.garcia@ 123456urjc.es

                Conflict of interest statement:The authors have declared that no conflict of interest exists.

                Article
                55429
                10.4317/jced.55429
                6522107
                b8c90dd0-336b-4267-9d9e-589199ccfc1e
                Copyright: © 2019 Medicina Oral S.L.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 March 2019
                : 16 November 2018
                Categories
                Review
                Oral Medicine and Pathology

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