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dc.contributor.advisorVanderah, Todd
dc.contributor.authorDavidson-Knapp, Rachel Beverly
dc.creatorDavidson-Knapp, Rachel Beverly
dc.date.accessioned2018-10-17T02:40:07Z
dc.date.available2018-10-17T02:40:07Z
dc.date.issued2018
dc.identifier.urihttp://hdl.handle.net/10150/630382
dc.description.abstractChronic pain affects approximately 100 million Americans for whom opioids are a popular therapy. While physicians and patients alike are apprehensive about using opioids due to their side effects including respiratory depression and addiction, 259 million opioid prescriptions were written in 2012. Although opioids are the best available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive or pain promoting, neurotransmitter Substance P (SP) and its corresponding receptor (NK1R) are found associated with dopamine neurons in the ventral tegmental area (VTA). Evidence exists suggesting that SP potentiates positive reinforcement of opiates leading to reward. Using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by inhibition of VTA GABAergic neurons. SP administered in the VTA significantly increases levels of dopamine in the nucleus accumbens (NAc), a reward processing center in the ventral striatum. Using CRISPR-Cas9 knockdown of NK1R in the VTA, we show this prevents the activation of opiate reward, corroborating the results from a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK1R antagonist, TY032, which was shown to inhibit acute and chronic pain in male rats. Importantly, our study found TY032 microinjection into the VTA did not result in an increase in extracellular dopamine release in the NAc. These data support the idea that targeting the dopamine reward circuitry and pain pathways with multifunctional opioid-NK1R compounds could be a path to developing analgesics that lack the potential for abuse.
dc.language.isoen
dc.publisherThe University of Arizona.
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
dc.titleINHIBITION OF OPIOID INDUCED REWARD VIA GENETIC AND PHARMACOLOGICAL MANIPULATIONS
dc.typetext
dc.typeElectronic Thesis
thesis.degree.levelbachelors
thesis.degree.disciplineHonors College
thesis.degree.disciplineNeuroscience & Cognitive Science
thesis.degree.nameB.S.
refterms.dateFOA2018-10-17T02:40:07Z


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