Date

8-2014

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

At its core, the brain is an integrator of sensory information. It undergoes dynamic changes depending on stimuli and environment, both of which directly affect sensory perception. In nociception, these changes manifest as descending inhibition or facilitation of pain. While either mode of modulation can be beneficial to an organism, pathological modulation can also occur. As a result, chronic pain can arise from a loss of descending inhibition, or a gain of descending facilitation of pain. By understanding the mechanisms that underlie chronic pain, we can begin to identify specific proteins that can be targeted for the development of novel therapeutics for chronic pain disorders. Equally important is to focus the studies on both male and female populations. To date, most studies use male subjects exclusively even in light of overwhelming data that chronic pain conditions manifest predominately in females.

GABAA signaling in the ventrolateral periaqueductal gray (vlPAG) is critical to the descending pain modulatory circuit. In the vlPAG, GABA provides tonic inhibition that when relieved, as in the case of endogenous opioid release or exogenous administration of morphine, activates the output neurons from the vlPAG to the rostral ventromedial medulla (RVM) in the descending pain modulatory pathway to inhibit pain responses in the spinal cord. GABA activates both phasic signaling through synaptic GABAA receptors and tonic signaling through extrasynaptic receptors. Extrasynaptic GABAA receptors have been identified in the vlPAG, but their role in chronic pain states has not been explored. The studies described show that the extrasynaptic GABAA receptor increases during chronic pain in females, and not males. Additional studies demonstrate differential regulation of genes between males and females during chronic inflammatory pain. These data identify GABAergic signaling in the vlPAG as sexually dimorphic, and these proteins may be a critical substrate for sex-based differences in nociception and chronic pain.

Central nervous system plasticity is suspected in chronic pain patients that do not have an obvious prior history of injury, but this has not been unequivocally demonstrated. A study herein presents the case that light may be used as a novel diagnostic test for measuring sensitization of central circuits in humans. Light produces pain in chronic pain patients that is not present in healthy controls. This is an important finding because light is a stimulus that is transmitted to the central nervous system without going through spinal pathways suggesting that central circuits are sensitized in chronic pain states. Further validation of light as a diagnostic tool will help in treatment decisions on a personal basis.

These findings contribute to our understanding of the central mechanisms underlying both chronic pain in general and the differential sensitivity of females to pain stimuli. The sexual dimorphism of chronic pain in the vlPAG between males and females indicates a critical role of the vlPAG in mediating the differences between chronic pain in the sexes. Future studies will examine how circulating estrogen affects the extrasynaptic GABAA, as well as the contribution of regulated genes to the development and maintenance of chronic pain in males and females.

Identifier

doi:10.6083/M4JS9P5N

Division

Neuroscience Graduate Program

School

School of Medicine

Available for download on Friday, December 31, 9999

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