Evolution of vertebrate opioid receptors: evidence from cloning and bioinformatics

Abstract

The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely‐related proteins belonging to the large superfamily of G‐protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth and newest member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This paper presents a comparative analysis of vertebrate opioid receptors using cloning studies from our lab, bioinformatic analyses, and data from recent human genome studies. Results indicate that it is likely that opioid receptors arose by two whole genome duplication events early in vertebrate evolution, that there is a vector of opioid receptor divergence such that receptors in mammals and humans exhibit a higher degree of opioid type‐selectivity, and that the MOR protein shows evidence of the most rapid adaptive evolution. Supported by a National Institutes of Health grant, DA0124482.