Multiple opiate receptors: déjà vu all over again

Abstract

The concept of multiple opioid receptors has changed dramatically since their initial proposal by Martin nearly 40 years ago. Three major opioid receptor families have now been proposed: mu, kappa and delta. Most of the opioid analgesics used clinically selectively bind to mu opioid receptors. Yet, clinicians have long appreciated subtle, but significant, differences in their pharmacology. These observations suggested more than one mu opioid receptor mechanism of action and led us to propose multiple mu opioid receptors over 20 years ago based upon a range of pharmacological and receptor binding approaches. A mu opioid receptor, MOR-1, was cloned about a decade ago. More recent studies have now identified a number of splice variants of this clone. These splice variants may help explain the pharmacology of the mu opioids and open interesting directions for future opioid research.

Introduction

The opiate field has a unique position in pharmacology and neuroscience. The opioid receptors were among the first neurotransmitter receptors to be identified and characterized in binding assays (Pert and Snyder, 1973, Simon et al., 1973, Terenius, 1973) and were one of the first to use a receptor to identify its endogenous ligand, the endogenous opioid peptides (Table 1) (Hughes et al., 1975, Hughes, 1975, Terenius and Wahlstrom, 1975, Pasternak et al., 1975a). Our understanding of these receptors and their endogenous ligands has mirrored the advancements of neuroscience, evolving from simple receptor binding assays, which were state of the art 30 years ago, to the cloning of these receptors and understanding them at the most basic molecular levels today.

From the beginning, our group has attempted to use the vast clinical experience with these agents to provide the direction for our laboratory work. Our focus over the years has been with the receptors, particularly the concept of multiple opioid receptors. The initial suggestion of multiple opioid receptors was based upon observations made with morphine and nalorphine combinations in patients (Lasagna and Beecher, 1954, Houde and Wallenstein, 1956). Nalorphine, in which the N-methyl group is substituted by an N-allyl group, was one of the earliest opioid antagonists. Its ability to reverse morphine actions was clearly demonstrated in clinical trials. However, as the relative dose of nalorphine to morphine was increased further, analgesia returned, illustrating a complexity in its pharmacology that had not been appreciated previously. Thus, nalorphine was a mixed agonist/antagonist capable of both reversing morphine analgesia and inducing analgesia itself at higher doses. These studies, which were performed almost half a century ago, led Bill Martin to suggest the existence of more than one opiate receptor, a concept he termed receptor dualism (Martin, 1967). In it, he proposed M and N receptors, corresponding to morphine and nalorphine receptors. Morphine was an agonist at the M receptor while nalorphine acted as an antagonist at the M receptor and an agonist at the N receptor.

Martin further refined his concept of multiple opioid receptors based upon the actions of series of drugs in the dog (Martin et al., 1976). In these studies, Martin again proposed a receptor for morphine, which he termed mu, as well as a receptor for the benzomorphan ketocyclazocine, which he termed kappa. He also suggested the existence of a third receptor, sigma. However, the concept of sigma receptors has evolved over the years (Pasternak et al., 1981, Wolozin et al., 1982, Walker et al., 1990). Although sigma₁ receptors modulate opioid actions (Chien and Pasternak, 1994, Pasternak, 1994, Chien and Pasternak, 1995a, Chien and Pasternak, 1995b), they are no longer considered opioid receptors. Indeed, cloning studies of the sigma₁ receptor from several species (Pan et al., 1998, Mei and Pasternak, 2001, Hanner et al., 1996, Kekuda et al., 1996, Seth et al., 1997) indicate a relatively small protein of approximately 25 kDa with two predicted transmembrane domains. Thus, the initial concept for multiple opioid receptors evolved from clinical trials with morphine/nalorphine combinations and classical pharmacological approaches. Their biochemical identification came afterwards.