THE UNIQUE BRAIN DIPEPTIDE KYOTORPHIN – FROM DISCOVERY TO NOWADAYS Isolation

Endogenous opioid peptides take part in various functions as hormones or neuromodulators. In 1979, Takagi and his co-workers identified a new morphine-like substance “kyotorphin” (Kyo) a dipeptide synthesized in specific brain regions. The highest levels were found in the lower brain stem and dorsal spinal cord areas closely associated with the pain regulatory system. The peptide binds to a specific receptor and induced Met-enkephalin release at rates of approximately four times the basal release. Literature data showed that Kyo receptor is identified in the membrane-preparations of the brain, which suggest that it plays a physiologically significant role in neurotransmission as a neurotransmitter/neuroregulator. + It is also transported by H -coupled peptide transporter PEPT2 across the BBB. The majority of research associated with kyotorphin relates to modulation of pain mechanisms via its ability to directly excite cortical neurons, and indirectly exert μand δ-opioid receptors to produce potent naloxone-reversible and long-lasting analgesia by releasing methionine-enkephalin (Met-Enk) and β-endorpins. However, Kyo has shown a wide dynamic range of bell-shaped dose-response curves in peripheral pain experiments. The effects of Kyo have been demonstrated to depend on different factors such as environmental temperature, animal species, experimental conditions, etc. They fall into two clearly identifiable groups: the ones, mediated via opioid peptides, and the opioid peptide-independent ones. It is certain that this peptide is a potent neuromodulator and its extensive actions, might, hopefully, stimulate consideration of possible therapeutic applications.