Opioids can induce dependence and elicit a withdrawal syndrome in users after the cessation of drug action. Opioid withdrawal is characterized by aversive symptoms that can elicit distress-relieving drug-seeking behavior and that thus contribute to the development and persistence of addiction. Animal models have been instrumental in scientists' evolving understanding of the critical role of limbic brain system N-methyl-d-aspartate (NMDA)-type glutamate receptors in both the opioid withdrawal response and learned aversive behaviors that may have persistent effects on drug-seeking behaviors. In addition, the NMDA receptors' involvement in opioid reward suggests that manipulating NMDA receptor function may prove beneficial in managing diverse components of opioid addiction.