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.