Dynorphin A 1-10

Dynorphin 1-17, (DYN 1-17) opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP) receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1-17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1-17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from lipopolysaccharide (LPS)-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1-17 and a specific range of fragments, with the greatest reduction observed with DYN 1-7 at a low concentration (10 nM). Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not other DYN 1-17 N-terminal fragments (DYN 1-10 and 1-11) on NF-κB/p65 nuclear translocation. DYN 1-17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1-7 at low concentrations (1 nM and 10 pM). These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1-17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.

Dynorphin A (1-13) and its analog dynorphin A (1-10) amide were applied intracerebroventricularly in male ICR mice. Both dynorphins did not reveal any analgesic activity in tail-flick test under normal (non-stressed) conditions. However, in combination with stress (forced swimming or whole body vibration) both dynorphins prolonged tail-flick latencies when compared with stressed saline controls. Naloxone inhibited the effect of dynorphins in forced swimming test. Neither dynorphin A (1-13) nor dynorphin A (1-10) amide increased tail-flick latencies when combined with weak immobilization stress. Our results suggest that the analgesic effects of dynorphins are potentiated by strong stressors.

This study examines the role of dynorphin-A(1-13) and dynorphin-A(1-10)-amide in the neuroendocrine regulation of anterior pituitary hormones in nonrestrained, adult male rhesus monkeys. The effects of these opioids on plasma concentrations of prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH) and growth hormone (GH) were assessed. Intravenous administration of dynorphin-A(1-13), 1-120 micrograms/kg, significantly increased plasma PRL levels. Average maximal increases of 90-230% occurred within 5 min and levels remained significantly elevated for up to 120 min. PRL response reached a plateau following the 30 micrograms/kg dose. Dynorphin-A(1-13) had no observable effects on plasma concentrations of LH, FSH, TSH or GH at any dose level studied. Administration of dynorphin-A(1-10)-amide produced significant dose-dependent increases in plasma PRL concentrations. Dose levels of 1-120 micrograms/kg produced mean peak increases from 100 to 230%, 5-10 min postadministration. Dynorphin-A(1-10)-amide had no significant effect on plasma concentrations of LH, FSH, TSH or GH. The increases in plasma PRL concentrations induced by dynorphin-A were naloxone-reversible. These results indicate a selective effect of dynorphin-A on the regulatory mechanisms of PRL secretion over that of other anterior pituitary hormones.