Date of Award

2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Opioids currently represent the best treatment option for severe and chronic pain conditions. Opioids while effective at controlling pain states also come with a number of side effects such as respiratory depression, urinary retention, dependence, tolerance, and opioid-induced hypernociception (OIH). OIH is a phenomenon in which opioids induce pain and this pain is often experienced at a site separate from the site of injury. Much research has been conducted investigating the mechanism of OIH, but the mechanism remains unsolved. One potential mechanism that has yet to be adequately explored is chemokines. Chemokines role in OIH is warranted given recent studies demonstrating the interaction between opioids and chemokines. Chemokines were originally thought to solely function in the immune system, but have recently been found to play a major role in the nervous system, as well as being implicated in a number of different pain models. Therefore, the purpose of these studies was to investigate a possible interaction between opioids and chemokines in the peripheral nervous system and the role this interaction plays in the development and maintenance of OIH. To do this, I tested for changes in expression of SDF1 and CXCR4 signaling in the dorsal root ganglion following repeated morphine administration. Secondly, I investigated if opioid or non-opioid signaling was involved in the development of OIH and which of these receptor signaling cascades was responsible for changes in SDF1/CXCR4 signaling in the dorsal root ganglion. These studies employed the use of a number of different methods including animal behavior, in situ hybridization, immunocytochemistry, and calcium imaging.

It was found that SDF1/CXCR4 signaling was indeed increased in OIH and that these changes in SDF1/CXCR4 signaling occur following activation of the mu opioid receptor. Additionally, OIH appears to be induced by both opioid and non-opioid receptor signaling. These results suggest that opioids are inducing a neuroinflammatory process that can be detrimental at anatomical sites separate from an injury. Therefore, to improve the analgesic effectiveness of opioids these off target effects must be considered and new treatments that can bypass these effects should be explored.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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