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The retina is able to adjust its signaling over a wide range of light levels. A functional result of this is increased visual acuity at brighter luminance levels, such as during the day, due to changes in the organization of retinal receptive fields. This process is commonly referred to as light adaptation. These organizational changes have been shown to occur at the level of the ganglion cells, the output neurons of the retina, which have shifts in their excitatory center-inhibitory surround receptive fields that increase their sensitivity to small stimuli. Recent work supports the idea that light-adapted changes in ganglion cell spatial sensitivity are due in part to inner retinal signaling changes, possibly including changes to inhibition onto bipolar cells, the interneurons at the center of retinal signal processing. However, it is unknown how inhibition to the bipolar cells changes with light adaptation, how any changes affect the light signal or what mediates the changes to the bipolar cells that have been suggested by previous reports. To determine how light adaptation affects bipolar cell inhibition, the inhibitory inputs to OFF bipolar cells were measured. OFF bipolar cells, which respond to the offset of light, in particular may be involved in retinal adaptation as they bridge dim- and bright-light retinal pathways. Their inputs were compared between dark- and light-adapted conditions to determine how any inhibitory changes affects their output onto downstream ganglion cells. We found that there was a compensatory switch from primarily glycinergic-mediated inhibition to OFF bipolar cells in the dark to primarily GABAergic-mediated inhibition in the light. Since glycinergic and GABAergic inhibition perform very different roles and are mediated by morphologically different cells, it is likely this switch underlies a change in the spatial distribution of inhibition to these cells. We found that the spatial inhibitory input to OFF bipolar cells became signific

Chronic pain has been estimated to impact the economy of the United States by an annual cost of $635 billion per year and to affect approximately 100 million Americans (1). Pain is the primary reason patients seek medical attention yet physicians have few options for therapies and there remains a vast unmet medical need for effective and safe analgesics. Most of the drugs clinically available today either have limited efficacy or a variety of unwanted side effects. Discovery of novel therapeutics has been challenging with scientists struggling to find ways to better translate research from the bench-top to the bedside. One impediment in this process has been differences in preclinical and clinical assessment of pain. Preclinical models have historically relied heavily on evoked or reflexive endpoints in non-verbal animals while clinical measures of pain have the advantage of assessing changes in self-reported pain ratings. It is likely, and data from the studies reported in this dissertation show, that mechanisms that underlie threshold responses to evoked stimuli differ from those mediating affective (i.e., aversive) qualities of pain. A further confound is that many effective analgesics are narcotics that carry risk of addiction. Fear of addiction and possibly misuse for chronic treatment of pain may result in undertreatment in many patients. The most clinically relevant question in the management of pain is whether or not a treatment improves the patient's quality of life. Here, we demonstrate that the aversiveness of ongoing pain can be assessed using motivated behavior (conditioned place preference; CPP) and neurochemical output (in vivo NAc microdialysis). Additionally, we assessed the mechanistic effects of three clinically relevant analgesics. Our results show that: (1) pain relief is rewarding and activates reward circuitry that differs from circuits mediating addictive qualities of opiates, and (2) that drugs that mimic the consequences of engagement of de