The life and times of endogenous opioid peptides: Updated understanding of synthesis, spatiotemporal dynamics, and the clinical impact in alcohol use disorder.

The opioid G-protein coupled receptors (GPCRs) strongly modulate many of the central nervous system structures that contribute to neurological and psychiatric disorders including pain, major depressive disorder, and substance use disorders. To better treat these and related diseases, it is essential to understand the signaling of their endogenous ligands. In this review, we focus on what is known and unknown about the regulation of the over two dozen endogenous peptides with high affinity for one or more of the opioid receptors. We briefly describe which peptides are produced, with a particular focus on the recently proposed possible synthesis pathways for the endomorphins. Next, we describe examples of endogenous opioid peptide expression organization in several neural circuits and how they appear to be released from specific neural compartments that vary across brain regions. We discuss current knowledge regarding the strength of neural activity required to drive endogenous opioid peptide release, clues about how far peptides diffuse from release sites, and their extracellular lifetime after release. Finally, as a translational example, we discuss the mechanisms of action of naltrexone (NTX), which is used clinically to treat alcohol use disorder. NTX is a synthetic morphine analog that non-specifically antagonizes the action of most endogenous opioid peptides developed in the 1960s and FDA approved in the 1980s. We review recent studies clarifying the precise endogenous activity that NTX prevents. Together, the works described here highlight the challenges and opportunities the complex opioid system presents as a therapeutic target.