Dynorphin A (1-13)

It was revealed in experiments on rats, that selective agonist of opioid kappa-receptors dynorphin A (1-13) has expressed antioxidant action in immobilization stress of different duration. It manifests itself with the decreases of the content of lipid peroxidation metabolites in liver tissue. It was shown, that the effect of this peptide on the activity of antioxidant enzymes superoxiddismutase and catalase depends on the stress duration. The stimulatory influence of peptide on catalase activity was shown in the rats after 3-hours immobilization, but the analogue effect of dynorphin was less in the animals after 6-hours or 12-hours stress. The stimulatory action of dynorphin A (1-13) on the superoxiddismutase activity was established in the rats after 6-hours or 12-hours immobilization within the experiment period, but peptide had no effect in the rats after 3-hours stress.

Dynorphins are important neuropeptides with a central role in nociception and pain alleviation. Many mechanisms regulate endogenous dynorphin concentrations, including proteolysis. Proprotein convertases (PCs) are widely expressed in the central nervous system and specifically cleave at C-terminal of either a pair of basic amino acids, or a single basic residue. The proteolysis control of endogenous big dynorphin (BDyn) and dynorphin A (Dyn A) levels has a profound impact on pain perception and the role of PCs remain unclear. The objective of this study was to decipher the role of PC1 and PC2 in the proteolysis control of BDyn and Dyn A levels using cellular fractions of spinal cords from wild-type (WT), PC1-/+ and PC2-/+ animals and mass spectrometry. Our results clearly demonstrate that both PC1 and PC2 are involved in the proteolysis regulation of BDyn and Dyn A with a more important role for PC1. C-terminal processing of BDyn generates specific peptide fragments dynorphin 1-19, dynorphin 1-13, dynorphin 1-11 and dynorphin 1-7, and C-terminal processing of Dyn A generates dynorphin 1-13, dynorphin 1-11 and dynorphin 1-7, all these peptide fragments are associated with PC1 or PC2 processing.

Experiments on rats showed that restraint stress is associated with an increase in plasma level of nonesterified fatty acids, total cholesterol, triglycerides, VLDL, and LDL. Administration of opioid peptides DSLET and DAGO alleviated stress-induced shifts in lipid metabolism. The concentrations of nonesterified fatty acids, total cholesterol, and triglycerides decreased and HDL content increased under these conditions. Treatment with dynorphin A (1-13) prevented a significant increase in the concentration of nonesterified fatty acids in blood plasma, but did not affect the content of triglycerides and total cholesterol. Hepatocyte growth factor had minor influence on the analyzed parameters. The observed effects can be related to the stress-limiting effect of opioids, in particular, attenuation of catecholamine influence on the lipid tissue and generation of LPO products that inhibit cholesterol-degrading enzyme.

In this study we investigated whether κ-opioid receptor stimulation by dynorphin A (1-13), a potent fragment of endogenous peptide, attenuated repeated stress-induced behavioral impairments in mice. In order to reduce the motivation to escape, mice were preexposed to inescapable electric footshock (day 0), and then dynorphin A (1-13) was administered to mice prior to the stress from the next day for 4 d (days 1-4). Dynorphin A (1-13) (1500 pmol/5 µL intracerebroventricular (i.c.v.)) attenuated the repeated stress-induced escape failures from the shock, and this improvement was inhibited by the pretreatment of nor-binaltorphimine (4.9 nmol/kg subcutaneously (s.c.)), a κ-opioid receptor antagonist. In the neurochemical experiments, we detected an increase in 5-hydroxyindoleacetic acid (5-HIAA) content, but not in serotonin (5-HT) content, and an increase in the 5-HIAA/5-HT ratio was observed in the amygdala of the group with footshock compared with the group without shock.