Biomedical Sciences ETDs

Publication Date

12-1-2012

Abstract

The focus of the work in this dissertation is to elucidate the efficacy of cannabinoid 2 receptor agonists, specifically targeting the spinal cord, for the treatment of chronic neuropathic pain. Chemical structures for all cannabinoid compounds utilized are displayed (Supplemental Figure A-1). As an orientation for the reader, the organization of this dissertation consists of five components: chapters 1 through 5. In the first chapter, a background is developed to acquaint one with the topics of chronic pain, and the use of cannabinergic compounds for chronic pain relief. This chapter is in the form of a review, and specifically addresses (1) the underlying differences in physiological processes during periods of acute pain compared to chronic pain, (2) the role of spinal cord glial cells under conditions of chronic inflammation, reflecting what is seen under chronic pain conditions, (3) the endogenous cannabinoid system; (4) evidence that specifically targeting the cannabinoid 2 receptor in the spinal cord may eventually be ideal for the treatment of chronic pain; and (5) the current clinical trial endeavors utilizing cannabinoid 2 receptor agonists. Following the review, evidence will be presented in support of the stated specific aims. Specific aim 1 of this dissertation will be in the form of two published manuscripts. The first manuscript, Chapter 2, explores the efficacy of one of the most widely utilized cannabinoid 2 receptor agonists, AM1241 following a peri-spinal, intrathecal injection. I display a dose-dependent effect, and the timecourse of the compounds ability to reverse pain symptoms. Further, using immunohistochemical techniques I detail a novel method of quantifying discrete anatomical changes in the immunostaining of inflammatory markers via the use of a computer assisted analysis of the entire spectral range of a variety of fluorescently-tagged antibodies. I refer to this method as 'spectral analysis'. This spectral analysis approach is more sensitive and accuate than conventional methods. Finally, this manuscript examines changes in critical factors known to mediate pathological pain in both the dorsal horn of the spinal cord and the dorsal root ganglia. The second manuscript, Chapter 3, explores the efficacy of a novel cannabinoid 2 receptor agonist AM1710 belonging to a chemically distinct classification of cannabinoid-like compounds following a peri-spinal, intrathecal injection. As in the first manuscript, for this compound, I display a dose-dependent effect, and the time course of the compound's ability to reverse pain symptoms. Additionally, spectral analysis methods are utilized to examine AM1710's ability to alter levels of critical factors known to mediate pathological pain, in both the spinal cord dorsal horn and the dorsal root ganglia. Finally, this manuscript characterizes AM1710's ability to act through anti-inflammatory pathways via peri-spinal glial cells within the meninges surrounding the spinal cord to block the development of neuropathic pain in a purely immune-mediated model of chronic pain. Specific aim 2 is in the form of a fourth manuscript to be submitted for peer-review in The Journal of Pain. The studies presented here within Chapter 4, are completed and provide evidence for AM1710's specificity to act via a restricted cannabinoid type 2 receptor, and not on the other classical cannabinoid receptor, the cannabinoid type 1 receptor. Further, the use of transgenic mice that lack functional cannabinoid 1 receptors uncovers a potentially novel and protective role of the endocannabinoid system under chronic pain conditions. Chapter 5 consists of a discussion of the main points from all the prior chapters to support the overarching thesis that the use of cannabinoid 2 receptor agonists is effective for the treatment of neuropathic pain. Additionally presented is a critique of some of the methods used to conduct experiments, and a supporting rationale for why these methods were selected. This dissertation concludes with potential future directions of this work, to further elucidate the endocannabinoid system for pain control.

Keywords

Pain, Glia, Spectral Analysis, Spinal Cord, Dorsal Root Ganglia, Cannabinoid

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Milligan, Erin

First Committee Member (Chair)

Wallace, James

Second Committee Member

Cunningham, Lee Anna

Third Committee Member

Bizzozero, Oscar

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