Opioid Research in Amphibians: A Unique Perspective on Mechanisms of Opioid Analgesia and the Evolution of Opioid Receptors

This review summarizes the work from our research group investigating mechanisms of opioid analgesia using the Northern grass frog, Rana pipiens. Over the last dozen years, we have accumulated data on the characterization of the behavioral effects after opioid administration, on radioligand binding studies using opioid agonist and antagonist ligands bound to amphibian brain and spinal cord homogenates, and by cloning and sequencing opioid-like receptor cDNA from amphibian CNS tissue. Relative analgesic potency of mu, kappa, and delta opioids is highly correlated between rats and frogs. Behavioral and binding studies using selective antagonists are not selective in amphibians. Three opioid-like receptor cDNAs were sequenced and are orthologs to mammalian mu, kappa, and delta opioid receptors. Phylogenetic analysis of the three types of opioid receptor cDNAs from all vertebrate species with full data sets gave a pattern of the molecular evolution of opioid receptors marked by divergence of mu, kappa, and delta opioid receptor sequences during vertebrate evolution. The order of receptor-type evolution is kappa, then delta, and most recently the mu opioid receptor. Finally, analyses suggest that conserved receptor domains determine the type selectivity of vertebrate opioid receptors.