Endogenous Opioids Contain Terminal Amino Acids that May Be Transformed to Catecholamines In Vivo and Modulate Pain

Feedback loops or compensatory mechanisms are present in a wide range of biological systems and processes. Here, we hypothesize that endogenous opioid peptides, such as endorphins and enkephalins, can be broken down and enzymatically converted to catecholamines (dopamine, norepinephrine, epinephrine) locally. Particularly, this proposed local production of norepinephrine may modulate analgesia through feedback mechanisms. A similar arrangement may occur for corticotropin-releasing factor and adrenocorticotropic hormone (hypothalamic-pituitary-adrenal axis mediation), insulin (blood glucose regulation), and angiotensin II (cardiovascular regulation). Endorphins, enkephalins, and dynorphins have an initial amino acid sequence of Tyr-Gly-Gly-Phe, where tyrosine (and possibly phenylalanine) could be enzymatically clipped from the peptide and converted to catecholamines locally, through the canonical biosynthetic molecular pathway for catecholamines. Spatially and possibly temporally precise conversion of these terminal amino acids to catecholamines may allow them to be produced "on demand" in specific regions of the brain, spinal cord, or periphery. This hypothesis is readily testable by infusing stable isotopically labeled opioids into the brain or periphery of model organisms, and observing through liquid chromatography-mass spectrometry whether the terminal amino acids of these opioids are converted to catecholamines.