{"id":{"repo_id":"arizona-thes","oai_identifier":"oai:repository.arizona.edu:10150/621568"},"canonical_url":"https://search.dev.ndltd.org/etd/arizona-thes/oai:repository.arizona.edu:10150/621568","repository":{"repo_id":"arizona-thes","name":"University of Arizona","base_url":"https://repository.arizona.edu/oai/request"},"display":{"title":"The Role of Substance P in Opioid Induced Reward","abstract":"Chronic pain affects approximately 100 million Americans. Opioids are the mainstay therapy for the treatment of chronic pain. 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 most efficacious available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive neurotransmitter, Substance P (SP) and its corresponding receptor (NK₁R), are not only found on pain pathways to promote pain but also found in the ventral tegmental area associated with dopamine neurons. Studies have shown that Substance P can potentiate positive reinforcement of opiates and may play a role in opioid reward. Here using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by ventral midbrain GABAergic neurons. Substance P administered to the VTA results in a significant increase in dopamine release in the nucleus accumbens (NAc). Using CRISPR-Cas9 knockdown of NK₁R in the VTA we prevent the induction of opiate reward as tested using a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK₁R antagonist bifunctional compound, TY032, which inhibits acute and chronic pain in male rats. Importantly, TY032 microinjection into the VTA did not increase extracellular dopamine release in the NAc and did not produce a positive CPP score. These data indicate dual targeting of the dopamine reward circuitry and pain pathways with multifunctional opioid-NK₁R compounds may be an effective strategy in developing future analgesics that lack the potential for abuse.","abstract_html":"Chronic pain affects approximately 100 million Americans. Opioids are the mainstay therapy for the treatment of chronic pain. 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 most efficacious available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive neurotransmitter, Substance P (SP) and its corresponding receptor (NK₁R), are not only found on pain pathways to promote pain but also found in the ventral tegmental area associated with dopamine neurons. Studies have shown that Substance P can potentiate positive reinforcement of opiates and may play a role in opioid reward. Here using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by ventral midbrain GABAergic neurons. Substance P administered to the VTA results in a significant increase in dopamine release in the nucleus accumbens (NAc). Using CRISPR-Cas9 knockdown of NK₁R in the VTA we prevent the induction of opiate reward as tested using a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK₁R antagonist bifunctional compound, TY032, which inhibits acute and chronic pain in male rats. Importantly, TY032 microinjection into the VTA did not increase extracellular dopamine release in the NAc and did not produce a positive CPP score. These data indicate dual targeting of the dopamine reward circuitry and pain pathways with multifunctional opioid-NK₁R compounds may be an effective strategy in developing future analgesics that lack the potential for abuse.","abstract_has_math":false,"creators":["Sandweiss, Alexander Jordan"],"institution":"The University of Arizona.","degree_name":"Ph.D.","degree_level":"doctoral","degree_discipline":"Graduate College","degree_department":null,"school":null,"contributors":[],"advisors":["Vanderah, Todd W."],"committee_chairs":[],"committee_members":["Khanna, Rajesh","French, Edward D.","Hruby, Victor H.","Rance, Naomi","Vanderah, Todd W."],"year":2016,"date_issued":"2016","date_published":"2016","updated_at":"2026-07-24T00:56:22Z","subjects":["Dopamine","Drug Abuse","Morphine","Neurokinin","Pain","Medical Pharmacology","Addiction"],"languages":["en_US"],"rights":["Copyright © 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."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10150/621568","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vanderah, Todd W."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Khanna, Rajesh","French, Edward D.","Hruby, Victor H.","Rance, Naomi","Vanderah, Todd W."]},{"key":"dc:creator","label":"Author","values":["Sandweiss, Alexander Jordan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2016-12-09T20:16:42Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2016-12-09T20:16:42Z"]},{"key":"dc:date.issued","label":"Date","values":["2016"]},{"key":"dc:publisher","label":"Institution","values":["The University of Arizona."]},{"key":"dc:type","label":"Dc Type","values":["text","Electronic Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Graduate College","Medical Pharmacology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Arizona"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Dopamine","Drug Abuse","Morphine","Neurokinin","Pain","Medical Pharmacology","Addiction"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright © 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."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10150/621568"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Chronic pain affects approximately 100 million Americans. Opioids are the mainstay therapy for the treatment of chronic pain. 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 most efficacious available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive neurotransmitter, Substance P (SP) and its corresponding receptor (NK₁R), are not only found on pain pathways to promote pain but also found in the ventral tegmental area associated with dopamine neurons. Studies have shown that Substance P can potentiate positive reinforcement of opiates and may play a role in opioid reward. Here using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by ventral midbrain GABAergic neurons. Substance P administered to the VTA results in a significant increase in dopamine release in the nucleus accumbens (NAc). Using CRISPR-Cas9 knockdown of NK₁R in the VTA we prevent the induction of opiate reward as tested using a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK₁R antagonist bifunctional compound, TY032, which inhibits acute and chronic pain in male rats. Importantly, TY032 microinjection into the VTA did not increase extracellular dopamine release in the NAc and did not produce a positive CPP score. These data indicate dual targeting of the dopamine reward circuitry and pain pathways with multifunctional opioid-NK₁R compounds may be an effective strategy in developing future analgesics that lack the potential for abuse."]},{"key":"dc:title","label":"Title","values":["The Role of Substance P in Opioid Induced Reward"]}]}],"canonical_facts":{"dc:contributor.advisor":["Vanderah, Todd W."],"dc:contributor.committeemember":["Khanna, Rajesh","French, Edward D.","Hruby, Victor H.","Rance, Naomi","Vanderah, Todd W."],"dc:creator":["Sandweiss, Alexander Jordan"],"dc:date.accessioned":["2016-12-09T20:16:42Z"],"dc:date.available":["2016-12-09T20:16:42Z"],"dc:date.issued":["2016"],"dc:description.abstract":["Chronic pain affects approximately 100 million Americans. Opioids are the mainstay therapy for the treatment of chronic pain. 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 most efficacious available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive neurotransmitter, Substance P (SP) and its corresponding receptor (NK₁R), are not only found on pain pathways to promote pain but also found in the ventral tegmental area associated with dopamine neurons. Studies have shown that Substance P can potentiate positive reinforcement of opiates and may play a role in opioid reward. Here using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by ventral midbrain GABAergic neurons. Substance P administered to the VTA results in a significant increase in dopamine release in the nucleus accumbens (NAc). Using CRISPR-Cas9 knockdown of NK₁R in the VTA we prevent the induction of opiate reward as tested using a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK₁R antagonist bifunctional compound, TY032, which inhibits acute and chronic pain in male rats. Importantly, TY032 microinjection into the VTA did not increase extracellular dopamine release in the NAc and did not produce a positive CPP score. These data indicate dual targeting of the dopamine reward circuitry and pain pathways with multifunctional opioid-NK₁R compounds may be an effective strategy in developing future analgesics that lack the potential for abuse."],"dc:identifier.uri":["http://hdl.handle.net/10150/621568"],"dc:language.iso":["en_US"],"dc:publisher":["The University of Arizona."],"dc:rights":["Copyright © 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:subject":["Dopamine","Drug Abuse","Morphine","Neurokinin","Pain","Medical Pharmacology","Addiction"],"dc:title":["The Role of Substance P in Opioid Induced Reward"],"dc:type":["text","Electronic Dissertation"],"thesis:degree_discipline":["Graduate College","Medical Pharmacology"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Arizona"]},"updated_at":"2026-07-24T00:56:22Z"}