Beta-Neoendorphin

The skin is the largest and a remarkably plastic organ that serves as a protective barrier against environmental stimuli and injuries throughout life. Skin injuries are serious health problems, and wound healing is a critical process to replace devitalized cellular and tissue structures. Although some endogenous opioids are known to be involved in the modulation of wound healing, it remains to be determined whether the β-neoendorphin (β-NEP), an endogenous opioid, has beneficial effects on wound repair in human keratinocyte. In this study, we found that β-NEP accelerated wound repair through activation of mitogen-activated protein kinase (MAPK)/Erk1/2 signaling pathways in human keratinocytes. Moreover, the wound healing effect of β-NEP is mainly through the acceleration of keratinocyte migration without affecting cell proliferation. Therefore, our studies reveal that β-NEP plays an important role in the regulation of wound repair and suggest a therapeutic strategy to promote wound healing using β-NEP.

Angiotensin-converting enzyme (ACE) has both somatic and testicular isozymes, the former possessing two catalytically active domains, amino-terminal and carboxyl-terminal, while the latter has only the carboxyl-terminal one. We compared hydrolysis processes of the nonapeptide beta-neoendorphin by the two isozymes of human ACE. Both isozymes hydrolyzed the peptide to Tyr1-Gly2-Gly3 by the sequential removal of carboxyl-terminal dipeptides in three consecutive steps. The rate constant values for the second step, conversion of beta-neoendorphin1-7 to Leu-enkephalin, by the somatic isozyme in the presence of 10 or 200 mM NaCl were 4-fold higher than those for the first step, conversion of beta-neoendorphin1-9 to beta-neoendorphin1-7. The k(cat) values of the somatic isozyme for beta-neoendorphin1-7 were 2-fold higher than those for beta-neoendorphin1-9, indicating that beta-neoendorphin1-7 is more rapidly hydrolyzed than beta-neoendorphin1-9. The rate constant value for the second step at 10 mM NaCl was 5-fold higher than that for the testicular isozyme. Similar extent of difference was also observed in k(cat) values for beta-neoendorphin1-7 between the two isozymes. These results suggest that the amino-terminal domain of the somatic isozyme mainly contributes to the conversion of beta-neoendorphin1-7 to Leu-enkephalin at a low NaCl concentration. Optimal chloride concentrations for the individual steps of beta-neoendorphin1-9 hydrolysis differed between the two isozymes.

The effects of beta-neoendorphin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. beta-neoendorphin (500 micrograms/kg) was injected iv, and the rats were decapitated serially. TRH, TSH, thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by means of a specific radioimmunoassay for each. Hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after beta-neoendorphin injection, and plasma concentrations tended to decrease, but not significantly so. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min. Plasma T4 and T3 levels did not change after the injection. Plasma ir-TRH and TSH responses to cold were significantly inhibited by beta-neoendorphin, but the plasma TSH response to TRH was not. Naloxone partially prevented the inhibitory effect of beta-neoendorphin on TSH release. In the haloperidol- or 5-hydroxytryptophan-pretreated group, the inhibitory effect of beta-neoendorphin on TSH release was prevented, but not in the L-dopa- or para-chlorophenylalanine-pretreated group. These drugs alone did not affect plasma TSH levels at the dose used. These findings suggest that beta-neoendorphin acts on the hypothalamus by inhibiting TRH release, which may be modified by amines of the central nervous system.