Trigeminal Inflammatory Compression in Rats: A Novel Orofacial Pain Model Open Access

Betarbet, Udayan Sandeep (2015)

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Background: Testing novel therapeutics for trigeminal neuralgia requires reproducible small animal models of chronic orofacial pain. Currently, the models of chronic orofacial pain in rats can cause excessive surgically-related damage that is not necessary to study trigeminal neuralgia therapeutics. The trigeminal inflammatory compression (TIC) model of orofacial pain has the potential to induce chronic orofacial pain with minimal surgically-related damage. This is the first study to investigate the use of the TIC surgery to induce chronic orofacial pain in rats.

Methods: The TIC surgery used in this study involved the placement of a length of chromic gut suture in direct and parallel contact with the infraorbital nerve of experimental rats. Following TIC surgery, increased sensitivity and pain-induced anxiety were characterized. Neuroinflammation of the infraorbital nerve in contact with chromic gut suture was quantified by macrophage and proinflammatory cytokine markers.

Results: Placement of the chromic gut suture in direct and parallel contact with the infraorbital nerve was correlated with reproducible mechanical allodynia in experimental rats. No evidence of pain-induced anxiety caused by the TIC surgery was detected by Light and Dark Box test during the ten week period of the study. Neuroinflammation caused by the TIC surgery was not detected by the presence of macrophages and interleukin-1β at ten weeks post-surgery.

Conclusion: The TIC model in rats is a promising model of chronic orofacial pain. With improved surgical placement of the chromic gut suture and additional behavioral assays of pain, the TIC model will be fully characterized by multiple dimensions of pain and may become a viable model to test novel therapeutics for trigeminal neuralgia.

Table of Contents

Introduction 1

Pain management and Trigeminal Neuralgia Research 1

Path of the Trigeminal Nerve: Whisker Pad Innervation to Brainstem 5

Animal Models of Chronic Orofacial 7

Neuroinflammation Mechanisms for Neuropathic Pain after Nerve Damage 14

Neuropathic Pain and Pain-Induced Anxiety 18

Behavioral Assays for Pain-Induced Anxiety 21

Trigeminal Inflammatory Compression Model In Rat Study Aims 23

Medical Ethics 24

Materials and Methods 27

Animals 27

Surgery 27

Light and Dark Box Test 28

Von Frey Filaments Test 29

Tissue Preparation 30

Immunohistochemical Analysis 31

Statistical Analysis 32

Results 33

Von Frey Hair Testing 33

Light and Dark Box Test Data 34

Immunohistological Staining of Trigeminal Nerve Tissue 38

Comparison of the Placement of Chromic Gut Suture Ten Weeks Post Surgery With Phenotypic Pain Response 41

Discussion 43

Von Frey Test and Mechanical Allodynia 44

Comparison of Von Frey Data to Alternative Chronic Orofacial Pain Models 44

Light and Dark Box 49

Comparison of Light and Dark Box Testing to Previous Models of Pain 50

Light and Dark Box Test: Need for More Testing 52

The Influences of Chronic Stress and Anxiety on the Pain Perception of Rats 54

Potential Chronic Stress Experienced by Rats in Study 54

Potential Anxiety Experienced by Rats Used in Study 55

Potential Effects of Chronic Stress and Anxiety on Pain Perception 56

Potential Effects of Chronic Stress on Pain Perception via Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction 57

Potential Effects of Stress on Von Frey Testing 58

Potential Effects of Anxiety on LDB Testing 58

Post-Operative Pain due to TIC Surgery 58

Neuroinflammation in the TIC model in Rats 60

Future Directions 62

Improvements to TIC Surgery 62

Improvements to Von Frey Testing 62

Improvements to LDB Testing 62

Improvements to Understand the Chronic Impact of Chromic Gut Suture on the ION 63

Proposed Alternative Behavioral Assays 63

Summary and Conclusion 66

Bibliography 68

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