Role for Tas2Rs in opioid addiction

Tas2Rs 在阿片类药物成瘾中的作用

• 批准号: 10177030
• 负责人: Paul J. Kenny
• 金额: $ 16.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177030
• 关键词: Affective; Alkaloids; Attenuated; Award; Behavioral; Biological Assay; Brain; CRISPR/Cas technology; Cells; Cleaved cell; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Consumption; Data; Development; Dose; Female; Funding; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic Transcription; Genome; Glutamates; Goals; Habenula; Ingestion; Injections; Intake; Intravenous; Knock-out; Manuscripts; Measures; Mediating; Modality; Molecular; Morphine; Motivation; Mus; Nature; Neurons; Nicotine; Nicotine Dependence; Nucleus solitarius; Opiate Addiction; Opioid; Opioid Receptor; Oxycodone; Pharmaceutical Preparations; Plant alkaloid; Plants; Procedures; Property; Psychological reinforcement; Publishing; Rattus; Receptor Signaling; Rewards; Role; Self Administration; Sensory; Signal Transduction; Site; Structure; Structure of choroid plexus; System; Taste Buds; Taste Perception; Therapeutic; Tissues; Withdrawal; addiction; alpha-gustducin; behavioral response; chromatin immunoprecipitation; conditioned place preference; conditioning; drug action; drug of abuse; experimental study; male; mu opioid receptors; novel; opioid use disorder; opioid withdrawal; receptor; response; sensor; single-cell RNA sequencing; transcription factor; transcriptome sequencing

Project Summary: Opioid drugs such as oxycodone are thought to act on addiction-relevant brain circuits exclusively through opioid receptors, most notably the μ opioid receptors (MORs). In common with other addictive drugs, morphine is a plant-derived alkaloid with an innately aversive bitter taste, a sensory modality that evolved to protect against ingestion of potentially noxious substances. Synthetic and semisynthetic opioids such as oxycodone also have alkaloid structures and a bitter taste. Taste 2 receptors (T2Rs) evolved to detect potentially poisonous alkaloids, but their potential involvement in the addiction-related behavioral actions of opioids is unknown to nicotine. Recently, we established a key role for T2Rs in regulating the aversive behavioral actions of nicotine that motivate nicotine avoidance and protect against addiction. Here, we will explore the role for T2Rs in regulating avoidance of opioids. T2Rs signal through a specialized G protein called α-gustducin, which is derived from the Gnat3 gene. In Experiment 1, we will assess the rewarding and aversive properties of oxycodone in wild-type and Gnat3-/- mice using conditioned place preference and avoidance conditioning. In Experiment 2, we will assess the reinforcing properties of oxycodone in wild-type and Gnat3-/- mice using the intravenous self-administration procedure. In Experiment 3, we will assess physical and affective components of opioid withdrawal in oxycodone-dependent wild-type and Gnat3-/- mice. In Experiment 4, we will determine which subtypes of T2Rs `cmehosense' oxycodone and other opioid drugs. These experiments have the potential to establish an entirely new class of receptors that can be targeted for the development of novel addiction therapeutics.

项目摘要： 阿片类药物如羟考酮被认为作用于成瘾相关的大脑回路 阿片受体是阿片类药物的主要受体之一，特别是μ阿片受体（MORs）。共同 与其他成瘾性药物一样，吗啡是一种植物衍生的生物碱， 味觉，一种进化来防止摄入潜在的 有毒物质合成和半合成阿片类药物，如羟考酮也有生物碱 结构和苦味。味觉2受体（T2 R）进化为检测潜在的有毒物质 生物碱，但它们在阿片类药物成瘾相关行为中的潜在参与是 不知道尼古丁最近，我们确定了T2受体在调节厌恶性 尼古丁的行为动作，促使尼古丁避免和防止成瘾。 在这里，我们将探讨T2 R在调节阿片类药物的回避中的作用。T2 Rs信号通过 称为α-gustducin的专门G蛋白，其来源于Gnat 3基因。实验 1，我们将评估羟考酮在野生型和Gnat 3-/- 小鼠使用条件性位置偏爱和回避条件。在实验2中，我们将 评估羟考酮在野生型和Gnat 3-/-小鼠中的强化特性， 静脉内自我给药程序。在实验3中，我们将评估物理和 羟考酮依赖性野生型和Gnat 3-/-小鼠中阿片类戒断的情感成分。 在实验4中，我们将确定T2 Rs的哪些亚型“cmehosense”羟考酮和其他亚型。 阿片类药物这些实验有可能建立一个全新的类 这些受体可以被靶向用于开发新的成瘾治疗剂。