Pain is the body's natural warning system to indicate one is in an environment highly detrimental to survival. The body's response to the sensation of pain is to immediately withdraw from this environment, ensuring continued survival. However, when pain lasts beyond the window in which it is useful, it no longer serves as a helpful warning system but instead degrades the quality of life. Chronic pain leads to patients seeking opioids to alleviate their condition and regain control of their

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... . A severe negative side effect of the use of opioids to treat chronic pain is the development of tolerance - a condition where, due to prolonged usage of opioids, the body fails to produce the desired levels of pain relief from the opioid dose. This necessitates increasing the dose of opioid and puts one at a greater risk of developing further negative side effects such as dependence and addiction. In the early 1990s we learned that tolerance to opioids, such as the drug morphine, is created and regulated in the brain. Specifically, it is created by adaptations within neurons in a midbrain region called the ventrolateral periaqueductal gray (v1PAG). This thesis has three central objectives - first to delve deeper into the v1PAG to better describe the neuronal adaptations that follow morphine tolerance, second to examine in greater specificity the contributions of a singular protein, Protein Kinase-C, in the development of morphine tolerance and third, to evaluate a novel non-opioid compound as a therapeutic for chronic pain. The studies in this thesis describe the nature and mechanism of adaptations that occur in v1PAG neurons following morphine tolerance and, in addition, describe a sex-specific non-opioid therapeutic for chronic pain.