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

Betarbet, Udayan Sandeep (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/mc87pq91d?locale=en
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Abstract

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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