Opioid Receptors and Peptide System Regulation in the Developing Nervous System

Abstract

The biochemical demonstration of opioid receptors was first established in 1973 (Pert and Snyder, 1973). Earlier attempts were difficult due to low levels of specific binding and high background binding. Although these early studies identified only a single type of receptor, pharmacological studies had already suggested the existence of multiple opiate receptor types (Martin et al., 1967). Evidence from behavioral, pharmacological and biochemical studies demonstrates the existence of several opiate receptor classes: mu (µ), delta (δ) and kappa (κ) (Lord et al., 1977; Chang and Cuatrecasas, 1979). The sigma (σ) receptor is no longer considered an opioid receptor and it has been suggested that it is the PCP site of the NMDA receptor (for reviews see Snyder, 1984; Zukin and Zukin, 1988). These receptor classes mediate diverse behavioral effects, exhibit different ligand selectivity patterns and have different distributions throughout the central and peripheral nervous systems. The µ, receptor is operationally defined as the high affinity site at which morphine-like opiates produce analgesia and a variety of other classical opiate effects. This receptor has been further subdivided into µ₁ and µ₂ (Pasternak et al., 1983). The δ receptor exhibits a higher affinity for the naturally occurring enkephalins (a class of shorter opioid peptides) than for morphine and was originally found in peripheral tissue such as the mouse vas deferens (Lord et al., 1977). The κ receptor is that site at which ketocyclazocine-like opiates produce analgesia, as well as their unique ataxic and sedative effects (Martin et al., 1976). It is also defined as a receptor highly selective for dynorphin (a 17-amino acid opioid peptide). Some researchers have demonstrated the existence of several κ receptor subtypes as well (Attali et al., 1982; Gouarderes et al., 1983; Zukin et al., 1988). Actions at all three of these sites are reversible by the opioid antagonist naloxone or naltrexone with increasing doses required going from µ to δ to κ receptors. The complex neuropharmacological actions of a given opioid would appear to reflect its interaction at a combination of these and other opioid receptor sites with varying potencies.