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 binds to all three of the
opioid receptor types (μ, δ, or κ), albeit with differing affinities.
Peptides derived from
proenkephalin and
prodynorphin are broadly distributed in the brain, and
mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used 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
opioid receptors to infer endogenous
peptide activity, and genetic knockout of
opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous
opioids, especially when similar results are found using different approaches. 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.