Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

针对新型阿片类药物使用障碍治疗的 Ghrelin 系统

基本信息

项目摘要

PROJECT SUMMARY Opioid overdose deaths and the rise in problematic opioid use patterns that indicate the development of opioid use disorder (OUD) have reached crisis levels in the United States. Behavioral interventions coupled with medication-assisted treatment (MAT), such as the partial opioid agonist buprenorphine, reduce repeated opioid overdoses and substantially improve the odds of successful recovery in OUD. While current MAT is a chief adjunct in the proper management of OUD patients, this crisis has crystalized the need to identify novel, non- opioid therapeutics for this chronic medical disorder. Neuroplasticity within the interconnected nodes of the meso-corticostriatal circuit contributes to the enhanced motivational attributes of abused drugs and drug- associated cues, key factors in sustained OUD and relapse. In this light, we identified ghrelin as an endogenous regulator of this therapeutically-relevant circuit. Ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to transduce several physiological and behavioral processes, including the reward- related effects of opioid agonists. We discovered that systemic administration of a GHS1αR antagonist/inverse agonist dose-dependently attenuated self-administration of the abused opioid analgesic oxycodone as well as oxycodone-seeking. During the UG3 phase, we will leverage this new knowledge and employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1αR antagonist/inverse agonist developed by Pfizer which has advanced into clinical trials. We will assess PF5190457 to block oxycodone intake without abuse liability and to suppress oxycodone withdrawal and relapse-like behaviors in male and female rats. We will also determine the drug metabolism and pharmacokinetics (DMPK) interaction between oxycodone and PF5190457 and brain penetrability of PF5190457 in opioid-experienced rats. With achievement of the UG3 preclinical milestones, we will work with NIDA to partner with Pfizer for Phase 1 clinical studies in non-treatment seeking OUD participants through assessment of the safety and tolerability of PF5190457 following oral oxycodone administration relative to placebo, the DMPK profile of oral oxycodone in OUD participants following PF5190457 (vs. placebo) dosing, and the subjective response to oral oxycodone following PF5190457 (vs. placebo). The second goal of the UH3 phase is to develop the preclinical data to support the prospect that PF5190457 may serve as an adjuvant therapy to reduce the dose of buprenorphine required for MAT. The small molecule GHS1αR antagonist/inverse agonist PF5190457 is a novel target for an OUD medication and achievement of the UG3 milestones demonstrating its effectiveness in the comprehensive preclinical analyses will provide the foundation for the UH3 to characterize PF5190457 as a potential treatment for OUD. The outcomes of the UG3/UH3 will have a sustained, powerful impact in our field with the prospect to validate a novel medication for OUD.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Kathryn A. Cunningham其他文献

Proteomics analyses: Peroxisome proliferator-activated receptor gamma agonist for chronic cocaine administration in rodents
  • DOI:
    10.1016/j.drugalcdep.2015.07.590
  • 发表时间:
    2015-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Nilesh S. Tannu;Joy Schmitz;Scott D. Lane;C. Green;Kathryn A. Cunningham;Robert Suchting;Juan Herrera;P.A. Narayana
  • 通讯作者:
    P.A. Narayana
Changes in brain white matter integrity after Ppar-gamma agonist treatment for cocaine use disorder
  • DOI:
    10.1016/j.drugalcdep.2016.08.316
  • 发表时间:
    2017-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Scott D. Lane;Khader M. Hasan;Benson Mwangi;P.A. Narayana;Jessica Vincent;F. Gerard Moeller;Joel Steinberg;Kelly Dineley;Kathryn A. Cunningham;Joy Schmitz
  • 通讯作者:
    Joy Schmitz
Novel bivalent serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptor ligands demonstrate distinct activities <em>in vitro and in vivo</em>
  • DOI:
    10.1016/j.drugalcdep.2015.07.1164
  • 发表时间:
    2015-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Rachel M. Hartley;Scott Gilbertson;Ying-Chu Chen;Noelle C. Anastasio;Robert G. Fox;Sonja J. Stutz;Cheryl Watson;Kathryn A. Cunningham
  • 通讯作者:
    Kathryn A. Cunningham
Effective connectivity of attentional bias in cocaine dependence
  • DOI:
    10.1016/j.drugalcdep.2016.08.405
  • 发表时间:
    2017-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    F. Gerard Moeller;Liangsuo Ma;Joel Steinberg;James Bjork;Scott D. Lane;P.A. Narayana;Thomas Kosten;Antoine Bechara;Joy Schmitz;Amanda E. Price;Kathryn A. Cunningham
  • 通讯作者:
    Kathryn A. Cunningham
The SoTL Scaffold: Supporting Evidence-Based Teaching Practice in Educational Development
SoTL 支架:支持教育发展中的循证教学实践
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Laura Cruz;Kathryn A. Cunningham;Brian Smentkowski;H. Steiner
  • 通讯作者:
    H. Steiner

Kathryn A. Cunningham的其他文献

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{{ truncateString('Kathryn A. Cunningham', 18)}}的其他基金

Novel Addiction Neurocircuits in Cocaine Taking
可卡因吸食中的新型成瘾神经回路
  • 批准号:
    10595681
  • 财政年份:
    2022
  • 资助金额:
    $ 223.03万
  • 项目类别:
Mechanisms of prenatal opioid exposure on brain and behavior
产前阿片类药物暴露对大脑和行为的机制
  • 批准号:
    10375927
  • 财政年份:
    2022
  • 资助金额:
    $ 223.03万
  • 项目类别:
Novel Addiction Neurocircuits in Cocaine Taking
可卡因吸食中的新型成瘾神经回路
  • 批准号:
    10375964
  • 财政年份:
    2022
  • 资助金额:
    $ 223.03万
  • 项目类别:
Mechanisms of prenatal opioid exposure on brain and behavior
产前阿片类药物暴露对大脑和行为的机制
  • 批准号:
    10657323
  • 财政年份:
    2022
  • 资助金额:
    $ 223.03万
  • 项目类别:
NOP Receptor Antagonist for OUD Pharmacotherapy
用于 OUD 药物治疗的 NOP 受体拮抗剂
  • 批准号:
    10085851
  • 财政年份:
    2020
  • 资助金额:
    $ 223.03万
  • 项目类别:
Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics
针对新型阿片类药物使用障碍治疗的 Ghrelin 系统
  • 批准号:
    10168769
  • 财政年份:
    2019
  • 资助金额:
    $ 223.03万
  • 项目类别:
Neural and Pharmacological Mechanisms of Abused Drugs
滥用药物的神经和药理学机制
  • 批准号:
    9404132
  • 财政年份:
    2016
  • 资助金额:
    $ 223.03万
  • 项目类别:
5-HT2 Receptor Allosterism in Cocaine Use Disorder
可卡因使用障碍中的 5-HT2 受体变构
  • 批准号:
    10445173
  • 财政年份:
    2015
  • 资助金额:
    $ 223.03万
  • 项目类别:
5‐HT2CR ALLOSTERIC MODULATORS AS NOVEL PHARMACOTHERAPY IN COCAINE USE DISORDER
5-HT2CR 变构调节剂作为可卡因使用障碍的新型药物治疗
  • 批准号:
    9271312
  • 财政年份:
    2015
  • 资助金额:
    $ 223.03万
  • 项目类别:
5‐HT2CR ALLOSTERIC MODULATORS AS NOVEL PHARMACOTHERAPY IN COCAINE USE DISORDER
5-HT2CR 变构调节剂作为可卡因使用障碍的新型药物治疗
  • 批准号:
    9480142
  • 财政年份:
    2015
  • 资助金额:
    $ 223.03万
  • 项目类别:

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