Morphine is a plant (opium poppy)-derived
alkaloid and one of the strongest known
analgesic compounds. Studies from several laboratories have suggested that animal and human tissue or fluids contain trace amounts of
morphine. Its origin in mammals has been believed to be of dietary origin. Here, we address the question of whether
morphine is of endogenous origin or derived from exogenous sources.
Benzylisoquinoline alkaloids present in human
neuroblastoma cells (SH-SY5Y) and human pancreas
carcinoma cells (DAN-G) were identified by GC/tandem MS (MS/MS) as
norlaudanosoline (DAN-G),
reticuline (DAN-G and SH-SY5Y), and
morphine (10 nM, SH-SY5Y). The stereochemistry of
reticuline was determined to be 1-(S). Growth of the SH-SY5Y cell line in the presence of (18)O(2) led to the [(18)O]-labeled
morphine that had the molecular weight 4 mass units higher than if grown in (16)O(2), indicating the presence of two atoms of (18)O per molecule of
morphine. Growth of DAN-G cells in an (18)O(2) atmosphere yielded
norlaudanosoline and (S)-
reticuline, both labeled at only two of the four
oxygen atoms. This result clearly demonstrates that all three
alkaloids are of biosynthetic origin and suggests that
norlaudanosoline and (S)-
reticuline are endogenous precursors of
morphine. Feeding of [ring-(13)C(6)]-
tyramine, [1-(13)C, N-(13)CH(3)]-(S)-
reticuline and [N-CD(3)]-
thebaine to the
neuroblastoma cells led each to the position-specific labeling of
morphine, as established by GC/MS/MS. Without doubt, human cells can produce the
alkaloid morphine. The studies presented here serve as a platform for the exploration of the function of "endogenous
morphine" in the neurosciences and immunosciences.