Opiate Pharmacokinetics: In Vivo Receptor Binding and Pharmacological Effects

Abstract

The discovery of a specific cerebral opiate receptor in 1973 (reviewed in reference 1) rapidly led to the detection of endogenous peptides as putative neurotransmitters/modulators associated with the opiate receptor (2). However, Martin et al. (3) presented the first pharmacological evidence that the opiate receptor system consists of several subpopulations of distinct receptor sites, and it was subsequently postulated that there are multiple opiate receptors and endogenous ligands (2), including Leu-enkephalin, Met-enkephalin, β-endorphin and dynorphin. In [³H]-ligand binding studies on rodent brain homogenates (4), at least three distinct binding sites were detectable; the μ, δ and κ/σ sites. Despite the rapid advance in opiate molecular pharmacology, several key questions concerning the molecular mechanisms remain unsolved. We are studying the problem with regard to which receptor subsites mediate the different pharmacological effects of the opiates. Effects include analgesia, dependence, tolerance and many other behavioral and peripheral changes that are seemingly unrelated to each other.