{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/79431"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/79431","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Characterization of Novel Alpha2/Alpha3 Subtype-Selective GABAA Receptor Positive Allosteric Modulators","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Lewter, Lakeisha"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Li, Jun-Xu","Neuroscience"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-04-04T20:32:53Z","date_published":"2019-04-04T20:32:53Z","updated_at":"2026-07-27T19:05:16Z","subjects":["neurosciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/79431","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Li, Jun-Xu","Neuroscience"]},{"key":"dc:creator","label":"Author","values":["Lewter, Lakeisha"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-04-04T20:32:53Z","2019","2019-01-18 17:14:30"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["neurosciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/79431"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Millions of individuals endure persistent pain. In the United States alone, about 30% of the population is estimated to suffer from chronic pain. In addition to the physical and emotional burden that chronic pain imparts, chronic pain represents a financial challenge, costing the nation up to $635 billion in treatment and lost productivity. Currently, the most widely used analgesics include µ-opioid agonists, anti-inflammatory steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs). While these analgesics are useful in some pain conditions, their use is limited due to lack of efficacy and various side-effects. Thus, the development of novel and effective analgesics remains a clinical need.Spinal GABAA receptors are thought to play a key role in pain processing. Previous studies have shown that local spinal application of benzodiazepine site ligands (that positively modulate GABAA receptor function) alleviates pain in both neuropathic and inflammatory pain models. Thus, GABAA receptors have received increasing attention as a promising target for the development of novel analgesics. Point mutation studies have aided in dissecting which GABAA α-subtypes mediate different effects of benzodiazepines. The α2 and α3 subtypes of GABAA receptors are associated with the analgesic effects of benzodiazepines. These studies have led to the development of novel subtype-selective GABAA positive allosteric modulators (PAMs). However, very few of the PAMs that are reported are truly selective for solely α2 and α3 subtypes. Therefore, much remains unknown regarding the full therapeutic potential of α2/α3 subtype-selective GABAA PAMs.Firstly, it was unknown whether α2/α3 subtype-selective GABAA PAMs were truly effective for attenuating pain due to their lack of α5 activity (a subtype that was initially thought to be necessary to produce analgesic effects). The studies presented in chapter 2 demonstrate that α2/α3 subtype-selective GABAA PAMs can produce robust analgesic effects, devoid of tolerance, in two different models of chronic pain. Additionally, α2/α3 subtype- selective GABAA PAMs can attenuate acute pain depending on the behavioral output and the degree of pain.Secondly, it was unknown whether GABAA PAMs and opioids were suitable for combination therapy. The studies done in chapter 3 demonstrate that α2/α3 subtype-selective GABAA receptor PAMs KRM-II-81 and NS16085 produced mainly additive and some supra- additive effects when combined with either oxycodone or morphine in CFA-treated rats (as demonstrated in the mechanical nociception assay). There were no infra-additive (antagonistic) effects observed in any of the fixed ratios between the GABAA PAMs and opioids.Thirdly, previous studies have shown that PAMs that are selective for α2/α3/α5 subtype- containing GABAA receptors have the ability to produce analgesia devoid of other undesired effects. The relationship between the analgesic effects and other off-target pharmacological effects of α2/α3 subtype-selective GABAA PAMs remained underexplored. The studies presented in chapter 4 demonstrated that while the analgesic effects of the nonselective midazolam were masked by other side-effects, α2/α3 subtype-selective GABAA PAMs were able to selectively produce analgesic effects, devoid of side effects such as sedation and cognitive impairment. Overall, these studies further support the clinical potential of α2/α3 subtype-selective GABAA PAMs as potential analgesics"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Characterization of Novel Alpha2/Alpha3 Subtype-Selective GABAA Receptor Positive Allosteric Modulators"]}]}],"canonical_facts":{"dc:contributor":["Li, Jun-Xu","Neuroscience"],"dc:creator":["Lewter, Lakeisha"],"dc:date":["2019-04-04T20:32:53Z","2019","2019-01-18 17:14:30"],"dc:description":["Ph.D.","Millions of individuals endure persistent pain. In the United States alone, about 30% of the population is estimated to suffer from chronic pain. In addition to the physical and emotional burden that chronic pain imparts, chronic pain represents a financial challenge, costing the nation up to $635 billion in treatment and lost productivity. Currently, the most widely used analgesics include µ-opioid agonists, anti-inflammatory steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs). While these analgesics are useful in some pain conditions, their use is limited due to lack of efficacy and various side-effects. Thus, the development of novel and effective analgesics remains a clinical need.Spinal GABAA receptors are thought to play a key role in pain processing. Previous studies have shown that local spinal application of benzodiazepine site ligands (that positively modulate GABAA receptor function) alleviates pain in both neuropathic and inflammatory pain models. Thus, GABAA receptors have received increasing attention as a promising target for the development of novel analgesics. Point mutation studies have aided in dissecting which GABAA α-subtypes mediate different effects of benzodiazepines. The α2 and α3 subtypes of GABAA receptors are associated with the analgesic effects of benzodiazepines. These studies have led to the development of novel subtype-selective GABAA positive allosteric modulators (PAMs). However, very few of the PAMs that are reported are truly selective for solely α2 and α3 subtypes. Therefore, much remains unknown regarding the full therapeutic potential of α2/α3 subtype-selective GABAA PAMs.Firstly, it was unknown whether α2/α3 subtype-selective GABAA PAMs were truly effective for attenuating pain due to their lack of α5 activity (a subtype that was initially thought to be necessary to produce analgesic effects). The studies presented in chapter 2 demonstrate that α2/α3 subtype-selective GABAA PAMs can produce robust analgesic effects, devoid of tolerance, in two different models of chronic pain. Additionally, α2/α3 subtype- selective GABAA PAMs can attenuate acute pain depending on the behavioral output and the degree of pain.Secondly, it was unknown whether GABAA PAMs and opioids were suitable for combination therapy. The studies done in chapter 3 demonstrate that α2/α3 subtype-selective GABAA receptor PAMs KRM-II-81 and NS16085 produced mainly additive and some supra- additive effects when combined with either oxycodone or morphine in CFA-treated rats (as demonstrated in the mechanical nociception assay). There were no infra-additive (antagonistic) effects observed in any of the fixed ratios between the GABAA PAMs and opioids.Thirdly, previous studies have shown that PAMs that are selective for α2/α3/α5 subtype- containing GABAA receptors have the ability to produce analgesia devoid of other undesired effects. The relationship between the analgesic effects and other off-target pharmacological effects of α2/α3 subtype-selective GABAA PAMs remained underexplored. The studies presented in chapter 4 demonstrated that while the analgesic effects of the nonselective midazolam were masked by other side-effects, α2/α3 subtype-selective GABAA PAMs were able to selectively produce analgesic effects, devoid of side effects such as sedation and cognitive impairment. Overall, these studies further support the clinical potential of α2/α3 subtype-selective GABAA PAMs as potential analgesics"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/79431"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["neurosciences"],"dc:title":["Characterization of Novel Alpha2/Alpha3 Subtype-Selective GABAA Receptor Positive Allosteric Modulators"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:16Z"}