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Spontaneous Behavioral Responses in the Orofacial Region: A Model of Trigeminal Pain in Mouse

Authors

  • Marcela Romero-Reyes DDS, PhD,

    Corresponding author
    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
    • M. Romero-Reyes, Department of Oral and Maxillofacial, Pathology, Radiology and Medicine, New York University College of Dentistry, 345 East 24th Street Room #827, New York, NY 10010, USA, email: marcela.romero@nyu.edu

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  • Simon Akerman PhD,

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Elaine Nguyen BS,

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Alice Vijjeswarapu BS,

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Betty Hom BS,

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Hong-Wei Dong MD, PhD,

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Andrew C. Charles MD

    1. From the NYU Orofacial and Head Pain Program, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York, NY, USA (M. Romero-Reyes); UCLA Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (M. Romero-Reyes, E. Nguyen, A. Vijjeswarapu, B. Hom, H-W. Dong, and A.C. Charles); UCSF Headache Group, Department of Neurology, San Francisco, CA, USA (S. Akerman); Laboratory of Neuro Imaging (LONI), Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA (H-W. Dong).
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  • Conflict of Interest: There are no conflicts of interest to report for any of the authors.

  • Funding Source: This research was supported by funding from the NIH National Institute of Drug and Abuse (NIDA) grant number DA-05010 (ACC), American Academy of Orofacial Pain research grant award 2008 (MRR), 2009 AHS/Migraine Research Foundation Thomas E. Heftler Migraine Research Award (MRR), and NYUCD startup fund (MRR). Funding source had no involvement in the experimental design or interpretation of the results.

Abstract

Objectives.— To develop a translational mouse model for the study and measurement of non-evoked pain in the orofacial region by establishing markers of nociceptive-specific grooming behaviors in the mouse.

Background.— Some of the most prevalent and debilitating conditions involve pain in the trigeminal distribution. Although there are current therapies for these pain conditions, for many patients, they are far from optimal. Understanding the pathophysiology of pain disorders arising from structures innervated by the trigeminal nerve is still limited, and most animal behavioral models focus on the measurement of evoked pain. In patients, spontaneous (non-evoked) pain responses provide a more accurate representation of the pain experience than do responses that are evoked by an artificial stimulus. Therefore, the development of animal models that measure spontaneous nociceptive behaviors may provide a significant translational tool for a better understanding of pain neurobiology.

Methods.— C57BL/6 mice received either an injection of 0.9% saline solution or complete Freund's adjuvant into the right masseter muscle. Animals were video-recorded and then analyzed by an observer blind to the experiment group. The duration of different facial grooming patterns performed in the area of injection were measured. After 2 hours, mice were euthanized and perfused, and the brainstem was removed. Fos protein expression in the trigeminal nucleus caudalis was quantified using immunohistochemistry to investigate nociceptive-specific neuronal activation. A separate group of animals was treated with morphine sulfate to determine the nociceptive-specific nature of their behaviors.

Results.— We characterized and quantified 3 distinct patterns of acute grooming behaviors: forepaw rubbing, lower lip skin/cheek rubbing against enclosure floor, and hindpaw scratching. These behaviors occurred with a reproducible frequency and time course, and were inhibited by the analgesic morphine. Complete Freund's adjuvant-injected animals also showed Fos labeling consistent with neuronal activation in nociceptive-specific pathways of the trigeminal nucleus after 2 hours.

Conclusions.— These behaviors and their correlated cellular responses represent a model of trigeminal pain that can be used to better understand basic mechanisms of orofacial pain and identify new therapeutic approaches to this common and challenging condition.

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