The Role of NMDA Receptors in Opiate Tolerance, Sensitization, and Physical Dependence A Review of the Research, A Cellular Model, and Implications for the Treatment of Pain and Addiction

When administered acutely, opiates such as morphine produce characteristic behavioral effects, including a decrease in pain responsiveness (analgesia) and an increase in pleasure (euphoria). Because of their profound ability to produce analgesia, opiates are the drugs of choice for the treatment of severe or chronic pain. Because of their ability to produce positive reinforcement and pleasure, these drugs are widely self-administered and, therefore, represent an important class of abused drugs. Long-term treatment with opiates, as well as other drugs of abuse, leads to three well-known consequences: tolerance, which is a decrease in an effect of a drug with chronic use; sensitization, which is an increase in an effect of drug with chronic use; and physical dependence, which is a physiological change produced by chronic use, such that the absence of the drug results in an unpleasant withdrawal syndrome* (1–3). Tolerance, sensitization, and physical dependence are important in both the clinical use of opiates and in their self-administration. For example, the development of tolerance to the analgesic effect of opiates may lead to the need to escalate the dose during the treatment of chronic pain, whereas tolerance to the euphorigenic effect may be a factor in the escalation of drug use in addicts (4). Conversely, tolerance to dose-limiting side effects may allow addicts to escalate drug intake and achieve greater euphorigenic effects. The development of sensitization is thought to be involved in the craving that occurs following chronic use of drugs of abuse and, therefore, critical to addiction (5,6). Finally, the avoidance of withdrawal in physically dependent individuals is considered to be an important factor in maintaining self-administration (2,4). Although tolerance, sensitization, and physical dependence have been widely studied, there is still an incomplete understanding of the neural mechanisms involved in their development and expression. Recent experiments suggest that excitatory amino acid systems and, in particular, N-methyl-D-aspartate (NMDA) receptors may have an important role in these phenomena. This review will explore the role of NMDA receptors in the behavioral changes that occur following long-term opiate administration, including tolerance, sensitization, and physical dependence. I will focus on opiates that act at the