Dynorphins

Discovery

Both Dyn and αNE are heptapeptide sequences that contain Leu-ENK (Tyr-Gly-Gly-Phe-Leu) in their N-termini. Isolation of these peptides from the porcine pituitary and hypothalamus was first reported in 1979.

Structure

Dyn A, Dyn B, and αNE are generated from a common precursor prodynorphin (PDYN, also known as proenkephalin-B, PENK-B) by proteolytic cleavage. Human PDYN contains three copies of Leu-ENK, which are flanked by dibasic amino acid residues. Other mammalian PDYN has a similar structure. In amphibians and fishes such as lungfish and shark, PDYN contains two copies of ENKs, Leu-ENK or Met-ENK, in addition to Dyn A, Dyn B, and αNE. Teleost PDYN also contains five ENKs, although two of them are unusual; one is present as a relic sequence and the other is Tyr-Gly-Gly-Phe-Ile. Thus, PDYN in the common ancestor may also have had five copies of ENKs. Several peptides with differential length are produced from PDYN. 

Gene, mRNA, and precursor

The human PDYN gene, PDYN, location 20p13, consists of four exons. Four cAMP responsive element (CRE)-like sites (DYNCRE1, 2, 3, and 4) are important for PDYN expression, and an AP-1 site, representing a specific target for Jun/Fos, and an SP-1-like domain, targeted by NGFI-A and a single AP-2 consensus site, have been proposed as promoter elements. Human PDYN contains 254 aa residues and comprises a signal peptide of 20 aa residue followed by a cysteine-containingN-terminal sequence and a region containing the repeated ENK sequences.

Synthesis and release

In the rat, the level of Pdyn mRNA expression has been shown to increase in the hypothalamus in response to osmotic challenge. In addition, seven daily injections of a dopamine agonist, apomorphine, caused an increase in the level of Pdyn mRNA expression in the striatum. Electrical stimulation in vivo decreased the expression of Pdyn mRNA in the dentate gyrus in the hippocampus.

Receptors

PDYN-derived peptides such as Dyn and αNE are agonists for KOR (also known as κ receptor, KOR-1, OP2, etc.), which is a subtype of opioid receptors belonging to the G protein-coupled receptor superfamily. Human KOR is located on chromosome 8 (8q11.2). Dyn-A (1–17) is considered to be an endogenous ligand for KOR.

Agonists and Antagonists

Nalfurafine, ethylketocyclazocine, hydromorphone, nalbuphine, morphine, fentanyl, etc., are agonists for human KOR. Buprenorphine, nalmefene, naltrexone, naloxone, alvimopan, etc., are antagonists for human KOR.

Biological functions

Based on the localization of KOR expression, dynorphins are involved in learning and memory, emotional control, stress response, and pain. Administration of high-efficacy KOR agonist caused depressant-like effects and anhedonia in rodents. Absence of KOR does not modify expression of the other components of the opioid system, and behavioral tests indicate that spontaneous activity is not affected in mutant mice. KOR is implicated in the perception of visceral chemical pain. KOR is critical for mediating the hypolocomotor, analgesic, and aversive actions of a KOR agonist. This receptor does not contribute to morphine analgesia and reward, but participates in the expression of morphine abstinence.

Clinical implications

Acute alcohol intoxication stimulates the release of Dyn. Dyn/KOR systems contribute to the negativereinforcing effects of alcohol based on the prodepressive effects of Dyn/KOR system activation, the antidepressant properties of KOR antagonists, and the involvement of KOR with the dysphoria produced by stress. The Dyn/KOR system is related to the pathogenesis and pathophysiology of several psychiatric disorders. Dyn/ KOR systems are recruited by various stimuli and act to shape neuronal activity, alter presynaptic neurotransmitter release, and decrease neuronal excitability. Changes in this system may contribute to symptom clusters that are shared by various psychiatric disorders.

Description

Dynorphin is an extraordinarily potent opioid peptide. To denote its powerful potency, the peptide was named “dynorphin” (“dyn” from the Greek dynamis=power and “orphin” for endogenous morphine peptide). α-Neoendorphin has been identified as a “big” leucine enkephalin (Leu-ENK) with potent opiate activity.

Clinical Use

Hydromorphone, morphine, fentanyl, etc., are used to treat moderate to severe pain. The antagonist buprenorphine is used to treat severe pain, and to ameliorate opioid dependence. Naltrexone is used alongside behavioral therapy both for opiate addiction and for alcohol dependency. Naloxone is used to reverse narcotic depression.