Investigating the Effect of Pharmacological Inhibition of Nav1.7 and 1.8 on Pain Responses and Cellular Plasticity after SCI Restricted; Files Only

Abstract

Spinal cord injury (SCI) affects nearly 309,000 people in the US with approximately 18,600 new cases yearly. Neuropathic pain resulting from SCI is often described as a shooting, burning, or stabbing sensation. There are currently no fully effective treatments available for neuropathic pain. Nociceptors transduce pain information and are known to become sensitized to stimuli after SCI. Voltage-gated sodium channels (VGSCs or Navs), a group of ion channels that are primarily responsible for the generation of an action potential, are found on nociceptors, making them a potential therapeutic target for the treatment of chronic neuropathic pain. This study examined the effect of pharmacologic inhibition of two Nav sub-types, Nav1.7 and 1.8 with PF-04856264 and A-803467, respectively, on pain responses in two pain models: complete Freund’s adjuvant (CFA)-induced inflammatory pain and SCI-induced neuropathic pain, and on cellular plasticity after SCI. In both the inflammatory and neuropathic pain model, wild-type mice were either injected with CFA or received a thoracic contusion SCI, which was followed by reflexive behavioral assessments of mechanical and thermal hypersensitivity from 1 to 35 days post injection or operation. Mice that received SCI were also evaluated for supraspinal mediated pain responses using operant pain and conditioned aversive paradigms. SCI mice were also evaluated for the recovery of locomotion. At the end of the behavioral assessments, the spinal cord and the dorsal root ganglia (DRGs), were collected for cellular assays for potential changes in inflammatory markers. Results suggest that following inflammatory pain, Nav1.7 inhibition attenuated mechanical hypersensitivity at later timepoints while Nav1.8 inhibition delayed the onset of pain. Following SCI, inhibition of Nav1.7 led to an improvement in locomotor function at sub-acute to chronic timepoints compared to immediately after SCI. Additionally, mechanical hypersensitivity was modestly attenuated but operant pain was significantly inhibited. Blocking Nav1.8 had minimal effect on neuropathic pain. Cellular assessments did not reveal a potential mechanism for Nav1.7 actions. Altogether, these results suggest that Nav1.7 and 1.8 likely play distinct roles in inflammatory and neuropathic pain, and that inhibition of Nav1.7 has beneficial outcomes by attenuating the maintenance of pain in both types of pain. 

Table of Contents

1. Introduction. 1

1.1 Overview of the Nervous System.. 1

1.2 Nociceptors & the Pain Pathway. 1

1.3 Spinal Cord Injury. 2

1.4 Inflammatory & Neuropathic Pain. 3

1.5 Voltage-Gated Sodium Channel Inhibition. 4

2. Hypothesis. 5

3. Methods. 5

3.1 Animals. 5

3.2 Drug Administration and Experimental Design. 6

3.2.1 CFA Administration. 6

3.2.2 Surgical Procedures. 6

3.3 Behavioral Assays. 7

3.3.1 Locomotor assessment 7

3.3.2 Assessment of mechanical hypersensitivity. 8

3.3.3 Assessment of thermal hyperalgesia. 8

3.3.4 Mechanical Conflict Avoidance Assessment 8

3.3.5 Conditioned Place Aversion (CPA) test 9

3.4 Cellular Assays. 10

3.4.1 Tissue Collection. 10

3.4.2 qRT-PCR and mRNA Quantification. 10

3.5 Statistical analyses. 11

4. Results. 11

4.1 Inflammatory Pain Model 12

4.1.1 Effect of Nav blockers on paw diameter after CFA treatment 12

4.1.2 Effect of Nav blockers on mechanical hypersensitivity after CFA treatment 12

4.1.3 Effect of Nav blockers on thermal hyperalgesia after CFA treatment 13

4.2 Neuropathic Pain Model 13

4.2.1 Effect of Nav blockers on locomotion after SCI 13

4.2.2 Effect of Nav blockers on mechanical hypersensitivity after SCI 13

4.2.3 Effect of Nav blockers on operant pain after SCI 13

4.2.4 Effect of Nav blockers on conditioned at level pain after SCI 14

4.2.5 Effect of Nav blockers on cellular plasticity after SCI 14

5. Discussion. 15

6. Conclusion. 19

7. Figures. 21

8. Funding Support 30

9. References 31

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell Biology, Neuroscience
Parola chiave	pain inflammatory pain hyperalgesia cellular plasticity neuropathic pain spinal cord injury mechanical conflict avoidance dorsal root ganglia voltage-gated sodium channel Nav channels allodynia
Committee Chair / Thesis Advisor	Dr. Sandra M. Garraway, Emory University
Committee Members	Dr. Patrick Cafferty, Emory University Dr. LaTonia Taliaferro-Smith, Emory University Dr. Donald Noble, Emory University Dr. George Staib, Emory University

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