Introduction

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, V-methyl-d-aspar-tate (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

* It is important to note that tolerance and sensitization occur to selected behavioral effects of a drug, rather than to all effects. Because of this, tolerance may occur to some effects, sensitization to others, and yet other effects may show no change with chronic use.

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

^-opioid receptor, because these drugs have been more widely studied than drugs acting on the 8 or k receptors and are more relevant to both addiction and the treatment of pain. The evidence suggests that NMDA receptors are widely involved in opiate-induced neural and behavioral plasticity, including the development of tolerance, sensitization, and physical dependence. Key research findings are discussed, as well as controversies in the field, a potential cellular model, and clinical relevance.

2. NMDA RECEPTORS

Although NMDA receptors are described in detail in other chapters in this volume, it will be helpful to offer a brief description here before entering into a detailed discussion of their involvement in opiate tolerance, sensitization, and physical dependence. NMDA receptors are a type of ionotropic excitatory amino acid receptor—large protein complexes, with a central ion channel and several sites to which neurotransmitters and drugs can bind and affect receptor activity. Key sites on the receptor include the competitive site, the glycine site, the noncompetitive site, and the polyamine site. Binding of an excitatory amino acid to the competitive site on the receptor complex opens the ion channel and allows calcium to flow into the neuron. When calcium enters the neuron, it can activate a variety of calcium-dependent enzymes and thereby modify neuronal function. Activation of NMDA receptors by competitive site agonists requires coactivation of the glycine site on the complex. Because glycine appears to be required for receptor function, it has been referred to as a coagonist of the NMDA receptor. The noncompetitive or phencyclidine (PCP) site is located within the ion channel. Drugs acting at this site block the open ion channel and prevent the influx of calcium, thereby inhibiting receptor function (These drugs are sometimes referred to as uncompetitive antagonists because their ability to block the receptor is dependent on receptor activation.) The final key site is the polyamine site; drugs acting at this site noncompetitively affect receptor activity (Fig. 1). The number of modulatory sites on the NMDA receptor complex allows for numerous pharmacological tools to explore the role of this receptor in physiology and behavior (7-13).

N-Methyl-d-aspartate receptors have been suggested to have a general role in neural and behavioral plasticity. Drugs that block these receptors have been found to interfere with several different types of neural and behavioral plasticity, including learning, long-term potentiation (LTP), long-term depression (LTD), neural development, kindling, and sensitization to pain (7,10-12,14-24). A notable observation in these studies is that NMDA receptor antagonists interfere with the development or acquisition of these phenomena, but not their expression. For example, NMDA receptor antagonists interfere with certain types of learning if administered during training, but they do not abolish learned responses if administered during testing. Similarly, these drugs block LTP if administered during its induction, but do not reverse this phenomenon after it is established. This pattern of results suggests that NMDA receptors are involved in the cellular changes that underlie the development of these forms of neural and behavioral plasticity. Evidence suggests that calcium influx and subsequent intracellular events associated with this influx mediate the role of NMDA receptors in neural and behavioral plasticity (7,10-12,19,20).

3. NMDA RECEPTORS AND THE DEVELOPMENT OF TOLERANCE TO OPIATE ANALGESIA

Over a decade ago, we began studies on the potential role of NMDA receptors in opiate tolerance and physical dependence. Reasoning that opiate tolerance and dependence were good examples of neural and behavioral plasticity, we hypothesized that NMDA receptors might be involved in these phenomena, in a manner similar to their involvement in learning and other forms of neural and behavioral plasticity. This hypothesis led us to predict that NMDA receptor antagonists would inhibit the development but not the expression of opiate tolerance and physical dependence. Initial studies on these phenomena suggested that this was, indeed, the case. In 1991, we reported that the potent

Extracellular

Extracellular

Intracellular

Fig. 1. Schematic diagram of the NMDA receptor complex. Key sites on the receptor complex at which drugs can bind and affect receptor activity are shown, including the competitive site, the glycine (coagonist) site, the non-competitive (PCP) site, and the polyamine site. Binding of an excitatory amino acid to the competitive site, together with binding of glycine to the coagonist site, opens the ion channel, allowing calcium ions to flow into the neuron. Influx of calcium appears to play a critical role in many of the cellular processes in which NMDA receptors are involved. See text for further discussion.

and selective NMDA receptor antagonist, MK-801, inhibited tolerance to the analgesic effect of morphine without affecting pain responsiveness on its own and without altering acute morphine analgesia (25). In these studies, MK-801 inhibited tolerance when coadminstered with morphine during the acquisition of this phenomenon, but did not affect morphine analgesia in tolerant animals. Thus, as predicted, the NMDA receptor anatagonist inhibited the development but not the expression of morphine tolerance. Marek and co-workers (26) reported similar findings in studies using MK-801 and the nonselective excitatory amino acid antagonist kynurenic acid. Inhibition of tolerance to the analgesic effects of morphine by NMDA receptor antagonists has been subsequently replicated by many different laboratories using a variety of different drugs, including noncompetitive NMDA receptor antagonists, competitive NMDA receptor antagonists, and NMDA receptor glycine-site antagonists (Tables 1 and 2). Similar findings have been obtained with drugs that affect a key second-messenger cascade downstream from NMDA receptor activation, nitric oxide (see Chapter 20). There is general agreement from these studies that NMDA receptor antagonists inhibit the development but not the expression of tolerance to the analgesic effect of morphine. Although a variety of drugs have been found to modify opiate analgesia and tolerance in other ways (69), the ability to inhibit the development, but not the expression, of opiate tolerance appears to be unique to NMDA receptor antagonists and drugs, such as nitric oxide synthase inhibitors, that inhibit the events subsequent to NMDA receptor activation (2,3,70-73). This pattern of action suggests that NMDA receptors are involved in the neural plasticity responsible for the acquisition of tolerance to the analgesic effect of morphine.

Table 1

Inhibition of the Development of Tolerance to the Analgesic Effects of Opiates by Noncompetitive NMDA Receptor Antagonists

Table 1

Inhibition of the Development of Tolerance to the Analgesic Effects of Opiates by Noncompetitive NMDA Receptor Antagonists

NMDA receptor antagonist

Species

Tolerance inductiona

Citation

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