Dynorphine

Dynorphin, often written dynorphin but occasionally encountered as dynorphine in older literature, refers to a class of endogenous opioid peptides derived from the prodynorphin (PDYN) gene. The principal active fragments are dynorphin A (1-17) and dynorphin B, produced by proteolytic processing of the prodynorphin precursor. These peptides have high affinity for the kappa-opioid receptor (KOR) and act as endogenous ligands that modulate pain, emotion, and neuroendocrine function.

Biogenesis and distribution: The PDYN gene is transcribed in neurons of various brain regions, including the hypothalamus, striatum (caudate-putamen), nucleus accumbens, amygdala, and periaqueductal gray, as well as in the spinal cord. Dynorphins are derived from prodynorphin through proteolysis, yielding several active peptides that can be released in response to neuronal activity.

Mechanism and function: Dynorphins primarily exert their effects via kappa-opioid receptors. KOR activation reduces the release of several neurotransmitters, notably dopamine in the mesolimbic pathway, contributing to analgesia and dysphoria. In addition to pain modulation, dynorphin signaling participates in stress responses, mood regulation, and appetite, and can influence endocrine signaling through the hypothalamic-pituitary-adrenal axis.

Clinical relevance: Altered dynorphin/KOR signaling has been implicated in mood disorders, stress-related responses, and substance use disorders. KOR agonism can produce analgesia but also dysphoria and aversion, while KOR antagonists are explored as potential treatments for depression and to reduce stress-induced relapse to drug seeking. Ongoing research seeks to clarify the therapeutic potential and safety of targeting the dynorphin/KOR system.