Associate Editor: M. Kimura
Regulations of opioid dependence by opioid receptor types

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Abstract

Three major types of opioid receptors, designated μ, δ, and κ, are widely expressed in the CNS. Development of selective receptor ligands and recent cloning of each receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each opioid receptor type. It is of interest to note that they include noncompetitive and allosteric interactions among their types. This review focuses on the functional interaction among these opioid receptor types that contribute to opioid dependence. Various studies provide arguments to support substantial roles for μ-opioid receptors and the possible involvement of δ-opioid receptors in the development of physical and psychological dependence on morphine. Noradrenergic transmission originating in the locus coeruleus is most likely to play the primary causal role in the expression of physical dependence on morphine. In contrast, many studies have pointed to the mesolimbic dopaminergic pathway projecting from the ventral tegmental area to the nucleus accumbens as a critical site for the initiation of psychological dependence on opioids. It is noteworthy as the broad existence of opposing interactions between μ/δ- and κ-receptors in the brain. The activation of κ-receptors leads to the suppression of unpleasant μ/δ-mediated side effects such as the rewarding effect. Considering the functional interaction among opioid receptor types, the co-administration of morphine-like compounds with κ-receptor agonists may constitute a preferable and superior approach to the treatment of pain with fewer side effects.

Introduction

Most classes of receptor are composed of multiple subpopulations that mediate varied physiological effects. Such multiple receptor types and subtypes are sufficiently closely related that they usually are capable of recognizing more than one endogenous ligand of the same class. Early studies of the bindings of various ligands have suggested the existence of a multitude of distinct types of receptors that can interact with opioid drugs or endogenous peptides. More evidence for the existence of opioid receptor types has been confirmed recently by molecular cloning, which already has proved valuable in furthering our understanding of the actions of opioid receptors at the molecular level. The three major opioid receptor types have been cloned and sequenced. In late 1992, a δ-opioid receptor was the first such gene to be cloned by two independent groups, Evans et al. (1992) and Kieffer et al. (1992). Following the cloning of the δ-opioid receptor, μ- and κ-opioid receptors have been cloned in the past several years (Chen et al., 1993a, Chen et al., 1993b, Li et al., 1993, Meng et al., 1993, Nishi et al., 1993, Yasuda et al., 1993, Fukuda et al., 1993, Wang et al., 1993, Wang et al., 1994, Zastawny et al., 1994). A cDNA clone encoding a structurally related receptor with amino acid similarity to these three receptor genes as high as 65% has been reported Bunzow et al., 1994, Chen et al., 1994.

Although all three major types of opioid receptors are able to mediate analgesia/antinociception, their individual binding profiles and other pharmacological activities clearly distinguish one from another. High-selective ligands that allowed for receptor-type labeling became available, as summarized in Table 1. Morphine from lanced unripe seed capsules of Papaver somniferum is the prototypical μ-opioid analgesic that serves as the standard drug against which all analgesics are compared in determining their relative analgesic potencies. It has been recommended as the drug of choice in the management of patients with chronic cancer pain by the World Health Organization Cancer Unit in its Cancer Pain Relief Program (Ventafridda et al., 1979). However, morphine also has undesirable effects, such as physical and psychological dependence.

As a clinical syndrome, physical dependence on opioids is readily discernible. The abstinence state is striking and peculiarly characteristic. The facets of physical dependence on opioids are the appearance of a highly characteristic syndrome following repeated administration, followed by discontinuance of an agonist (abrupt withdrawal or abstinence), or followed by precipitation through administration of competitive opioid antagonists, resulting in withdrawal signs. In order to ascertain physical dependence on opioids, the validity and significance of using the methodology of precipitation by antagonists have gained almost universal acceptance (Bhargava, 1994).

Opioid receptor agonists also exert marked effects on mood and motivation. They produce euphoria in humans, and function as positive reinforcers in a variety of species; i.e., they maintain those behaviors that lead to their administration. The rewarding effects of these drugs may become so marked that they become the primary stimuli for motivating behavior, and thus, the process of compulsive drug seeking or addiction ensues Koob, 1992, Van Ree et al., 1999. Both operant and classical conditioning techniques have been used to examine psychological dependence on opioids.

It is well known that various types of opioid receptors are involved in the development of psychological and physical dependence on opioids. It, therefore, is worthwhile to investigate the role of each opioid receptor type and the functional interaction among the types in the development of opioid dependence. This review attempts to summarize the interaction among opioid receptor types on the development of opioid dependence.

Section snippets

The observed signs/symptoms of abstinence syndrome in morphine-dependent subjects

Chronic administration of morphine results in the development of physical dependence, as evidenced by the appearance of distressing physical symptoms. The symptoms of withdrawal can be induced either by abrupt termination of morphine treatment or by injecting an opioid receptor antagonist, such as naloxone, nalorphine, naltrexone, or levallorphan. The signs and symptoms may simulate a severe cold, and usually include nasal discharge, lacrimation, chills, goose pimples, and muscular aches.

Models for the study of motivational effects elicited by opioids

Like other abused drugs, μ-opioid receptor agonists, such as morphine, heroin, and methadone, act as rewarding stimuli when administered to animals. For example, monkeys have been shown to intravenously self-administer heroin rather than saline when given a choice. Furthermore, μ-opioid receptor agonists can lower the electric current threshold for intracranial electrical self-stimulation, indicating an ability of the opioid to facilitate the central reward mechanism itself. These positive

Concluding remarks

Opioid receptors are the primary sites of action for opioid alkaloids and endogenous opioid peptides, which have a wide variety of pharmacological and physiological effects. The successful cloning of cDNAs for opioid receptors has provided evidence for the existence of three major opioid receptor types in the CNS, designated μ, δ, and κ. Although their individual molecular structures and physiological functions clearly distinguish them, it is of interest to note that these distinct opioid

Acknowledgements

This work was supported in part by grants from the Ministry of Health and Welfare of Japan and the Ministry of Education, Science, Sports, and Culture of Japan to T. Suzuki.

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