Functionally selective, or biased, opioid ligands for several opioid receptors exist and hold promise as improved therapeutics with fewer liabilities.

Crystal structures of the inactive states for all four receptors (μ, δ, κ, and nociceptin) and the active state of μ have been elucidated and these structures are accelerating the structure-guided design of novel opioid ligands.

Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled palette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemogenetic and optogenetic tools, and new mouse lines, are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics.

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Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors.

Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice.

Exploring the biology of G protein-coupled receptors from in vitro to in vivo.

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.

The role of a sodium ion binding site in the allosteric modulation of the A(2A) adenosine G protein-coupled receptor.

Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of β-arrestin and arrestin in the β 2 -adrenergic receptor and rhodopsin systems.

Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus.

Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor.

The effects of morphine and morphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog.

Glossary

the term has been used to describe the processes by which macromolecules (proteins such as receptors) can be engineered to interact with previously unrecognized small molecules. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a commonly used example in which GPCRs have been engineered to respond to inert ligands CNO or salvinorin B.

is an enzyme derived from the P1 bacteriophage. The enzyme is a member of the integrase family of site-specific recombinases and it is known to catalyze the site-specific recombination event between two DNA recognition sites (loxP sites). This 34 base pair (bp) loxP recognition site consists of two 13 bp palindromic sequences flanking an 8 bp spacer region. The products of Cre-mediated recombination at loxP sites are dependent upon the location and relative orientation of the loxP sites.

Designer Receptors Exclusively Activated by Designer Drugs represent a typical GPCR-based chemogenetic tool.

similar to cre, is a site-directed recombination technology, to manipulate an organism's DNA under controlled conditions in vivo. It is analogous to Cre-lox recombination, but involves the recombination of sequences between short flippase recognition target (FRT) sites by the recombinase (Flp)-derived from the 2 μm plasmid of baker's yeast.

a technique that involves the use of light to control cells in living tissue, typically neurons, which have been genetically modified to express light-sensitive proteins.

based on the wording of Har Gobind Khorana and others, chimeric GPCRs have been developed that replace the intracellular loops of bovine rhodopsin with specific intracellular components of GPCRs, including opioid, adrenergic, adenosine, and serotonergic versions.

involves two methods to engage biological processes. One utilizes an uncaging process to make a compound biologically active in response to light; the other uses light-sensitive proteins such as rhodopsin that can excite, inhibit, or engage a particular cell type.