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Papers of the Week

Papers: 30 May 2020 - 5 Jun 2020

Pharmacology/Drug Development

2020 Jun 02

Mol Pharmacol

Five decades of research on opioid peptides: Current knowledge and unanswered questions.


Fricker LD, Margolis E, Gomes I, Devi LA
Mol Pharmacol. 2020 Jun 02.
PMID: 32487735.


In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, ~20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors (proenkephalin, prodynorphin, and proopiomelanocortin) by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides bind to all three of the opioid receptor types (mu, delta, kappa), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been utilized to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e. to excised tissue) or in vivo (in animals), using antagonists of specific opioid receptors to infer endogenous peptide activity, and using positron-emission tomography (PET) to detect a change in receptor availability, a sign of peptide release. While each of these approaches have weaknesses, certain observations have been consistent across modalities thereby adding to our current understanding of the function of endogenous opioids. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.