ABSTRACT
The pharmacological identification of types of opioid receptors has made rapid progress due, in part, to the increasing availability of highly selective opioid agonists and antagonists. Such compounds have been critical in allowing investigators to develop reasonable confidence that particular opioid receptor types are involved in the transduction of specific effects, such as antinociception. As with many other systems, it is now clear that the opioid receptors can all be linked to the mediation of particular effects, and that multiple receptor involvement in a particular effect is the rule, rather than the exception. The recent cloning of three types of opioid receptors (the ¡x, 8 and K opioid receptors) (Evans et al, 1992; Kieffer et al, 1992; Chen et al, 1993; Minami et al, 1993; Yasuda et al, 1993) from tissues derived from mouse or rat provides a long-awaited structural basis for the classification of opioid receptor types. It is now known that these cloned receptors share structural features typical of the members of the superfamily of G-protein linked receptors, and that these three receptor types share a surprising degree of homology. Whether multiple subtypes of these three opioid receptors will be identified or whether other explanations exist for the many pharmacological studies which suggest that the opioid receptor types can be further classified into subtypes remains to be determined. Though future work will be necessary to elucidate this issue, the pharmacological classification of opioid receptors according to type, and to subtype, nevertheless allows the continuation of efforts aimed at the development of highly selective molecules which may prove to be of clinical importance in specific applications. Of particular interest is the pharmacological identification of subtypes of opioid 8 and K receptors, and the possible importance of such receptor types in the development of appropriate molecules for the relief of pain, particularly in the potential treatment of chronic or persistent pain states or perhaps in selected conditions such as those involving visceral pain. This summary will attempt to
constipation or other adverse gastrointestinal effects (Sheldon et al., 1990), and with minimal development of physical dependence (Cowan et al., 1988). Additionally, the specific mechanism of the gastrointestinal action of 8 agonists may be particularly significant for clinical management of disorders such as diarrhea and the pain of cholecystitis (Sheldon et al., 1990). Further, 8 agonists are known to produce potentially beneficial modulatory effects (i.e., enhancement of potency and efficacy) on standard opiates such as morphine (Vaught and Takemori, 1979; Jiang, Mosberg, and Porreca, 1990). For 8 antagonists, potential clinical applications include the delay or prevention of tolerance and physical dependence to morphine and other /¿-acting opioids (Abdelhamid et al., 1991; Miyamoto, Portoghese and Takemori, 1993), and possibly the blockade of the reinforcing properties of substances of abuse such as cocaine in mice and rats (Menkens et al., 1992; Reid et al., 1993). For K agonists, potential clinical advantages include analgesia with greatly reduced likelihood of physical dependence (e.g., Cowan et al., 1988) and with minor, or no, adverse gastrointestinal effects (Porreca et al., 1983; Sheldon et al., 1990). Recent findings also suggest that compounds with K agonist activity may actually have significant therapeutic utility in particular states of gastrointestinal paresis (Riviere et al., 1993). Finally, the potential therapeutic implications of partial 8 and K agonists has yet to be fully explored.
