Opiate-induced analgesia: contributions from mu, delta and kappa opioid receptors mouse mutants

The three opioid receptors, mu, delta and kappa all mediate analgesia, and knockout mice with opioid receptor deletion have proven unique tools to investigate in vivo opioid pharmacology. Since a few years, a number of new mouse lines have been engineered, with several distinct mutations of the mu receptor, to assess the role of specific amino acid residues or peptidic sequences of this receptor in analgesia and tolerance. The analysis of analgesia in mice deleted in kappa receptor and triple mu/delta/kappa receptor knockout mice have provided advances in opioid-induced analgesia. Also, the global and conditional deletion of the delta receptor in peripheral nociceptive neurons has revealed the participation of the targeted receptors in opioid-induced analgesia. Another approach for the study of opioid receptors is the visualization of these receptors in vivo, by engineering of knock-in mice with fluorescently tagged receptors. A mouse line with a fluorescent delta receptor has allowed live imaging of this receptor in behavioral paradigms and first studies on ligand-biased agonism at this receptor in vivo. The studies with mutant mouse lines for opioid receptors, combined with novel molecular and pharmacological approaches, will allow to develop novel strategies for opioid-based analgesia. This review summarizes the different genetically modified mouse lines for opioid receptors as well as the data and concepts inferred from analgesia results on these mutant mouse lines.