Date of Award

5-11-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Anne Z. Murphy

Second Advisor

Geert de Vries

Third Advisor

Michael Morgan

Fourth Advisor

Marise Parent

Abstract

Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, to date, no studies have examined the role of glia activation within this region. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This dissertation seeks to address the lack of knowledge regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance by (1) Characterizing the effects of chronic morphine and peripheral inflammatory pain on vlPAG glial cell activity; (2) Investigating the role of glia activation within the vlPAG in the development of morphine tolerance; (3) Characterizing the role of the glial receptor TLR4 within the vlPAG in the development of morphine tolerance; and (4) Characterizing the glia to neuron signaling mechanisms involved in the development of morphine tolerance. These experiments, together, provide novel information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.

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