Role for Tas2Rs in opioid addiction

项目总结： 阿片类药物，如羟考酮，被认为作用于与成瘾有关的大脑回路 仅通过阿片受体，最著名的是μ阿片受体(MORS)。共同之处 与其他成瘾药物一样，吗啡是一种从植物中提取的生物碱，带有一种天生讨厌的苦味 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，如羟考酮也含有生物碱。 结构和苦味。味觉2受体(T2Rs)进化为检测潜在有毒物质 生物碱，但它们可能参与阿片类药物成瘾相关的行为行为 尼古丁不知道的。最近，我们确定了T2Rs在调节厌恶者中的关键作用 尼古丁的行为行为，刺激尼古丁的回避并防止上瘾。 在这里，我们将探讨T2Rs在调节阿片类药物避免中的作用。T2RS信号通过一个 一种名为α-Gustducin的特殊G蛋白，源自GNA3基因。在实验中 1，我们将评估羟考酮在野生型和GNat3-/-中的奖赏和厌恶特性 使用条件性位置偏爱和回避条件反射的小鼠。在实验2中，我们将 评估羟考酮在野生型和GNA3-/-小鼠中的增强特性 静脉注射自我给药程序。在实验3中，我们将评估身体和 羟考酮依赖野生型和GNA3-/-小鼠阿片类药物戒断的情感成分。 在实验4中，我们将确定哪些亚型的T2Rs‘cmehosense’羟考酮和其他 阿片类药物。这些实验有可能建立一种全新的 受体可作为开发新的成瘾治疗药物的靶点。

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.