Enterostatin (VPDPR) has anti-analgesic and anti-amnesic activities.

Enterostatin (VPDPR), an anorexigenic peptide derived from the amino terminus of procolipase, significantly inhibited analgesia induced by the mu-opioid agonist morphine (5 mg/kg, s.c.) after i.c.v. administration to mice at a dose of 100 nmol. On the other hand, VPDPR (approximately 200 nmol, i.c.v.) did not attenuate analgesia induced by the kappa-opioid agonist D-Phe-D-Phe-D-Nle-D-Arg-NH2 (100 microg/mouse, i.c.v.) or delta-opioid agonist DTLET (4 nmol/mouse, i.c.v.). VPDPR (100 nmol, i.c.v.) significantly improved amnesia induced by scopolamine (0.2 mg/kg, i.p.) in mice. However, VPDPR did not enhance memory in normal mice at the same dose.

Designing of an orally active complement C3a agonist peptide with anti-analgesic and anti-amnesic activity.

Complement C3a is an anti-opioid peptide, having anti-analgesic and anti-amnesic effects after intracerebroventricular administration. However, the peptide is inactive after oral administration. Orally active C3a agonist peptide was designed based on the structure of oryzatensin, a C3a agonist peptide derived from rice albumin. Tyr-Pro-Leu-Pro-Arg, a pentapeptide at the carboxyl terminus of oryzatensin is the minimally essential structure for exerting C3a activity. Due to the affinity for mu-opioid receptor, both oryzatensin and Tyr-Pro-Leu-Pro-Arg showed analgesia after intracerebroventricular administration in mice which was blocked by the opioid antagonist naloxone. Tyr-Pro-Leu-Pro-Arg lost opioid activity by substitution the amino terminus tyrosine with other hydrophobic residues. Among the newly designed peptides, Trp-Pro-Leu-Pro-Arg was found to possess the strongest C3a activity. The peptide antagonized morphine-induced analgesia at 300 mg/kg after oral administration and also improved scopolamine- and ischemia-induced amnesia in a step-through passive avoidance test.

Retro-nociceptin methylester, a peptide with analgesic and memory-enhancing activity.

Retro-nociceptin methylester (retro-Noc-ME), which has an oppositely directed structure to that of nociceptin, showed weak affinity for nociceptin receptor and antagonized nociceptin-induced inhibition of contraction in a guinea pig ileum (GPI) assay. The peptide induced analgesia after intracerebroventricular (i.c.v.) administration at a dose of 100 nmol per mouse. Analgesia was not blocked by the opioid antagonist naloxone, which suggests that the analgesia is not mediated by opioid receptor. Furthermore, analgesia caused by retro-Noc-ME was not attenuated after repeated administration, that is, there was an absence of tolerance. The peptide improved learning ability after i.c.v. administration in a step-through experiment in mice.

Anti-analgesic and anti-amnesic effect of complement C3a.

In the present study, we found that complement C3a exerted central effects after intracerebroventricular administration in mice. At doses of 3 and 10 pmol/mouse, the peptide showed an antagonistic effect on analgesia induced by morphine and U-50488H, known to be mu- and kappa-opioid receptor agonists, respectively. Moreover, complement C3a improved scopolamine- and ischemia-induced amnesia at a dose of 10 pmol/mouse. Anti-analgesia was not observed by C3a des-Arg at 10 pmol/mouse. The present findings suggest that complement C3a may act as a peptide with anti-opioid activity in the central nervous system.

Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein.

Conditions for the release of beta-casomorphin-7 from bovine beta-casein by gastrointestinal proteases in vitro were investigated. beta-Casomorphin-7 was released only from a genetic variant of beta-casein containing a His residue at the 67th position of the peptide chain. Elastase cleaved the peptide bond between Ile66 and His67, releasing the carboxyl terminus of beta-casomorphin-7. Pepsin and leucine aminopeptidase were required to release the amino terminus of this peptide. beta-Casomorphin-9, -13, and -21 also were isolated, and their opioid activities were measured. In this study, we also isolated a novel opioid peptide neocasomorphin-6 (Tyr-Pro-Val-Glu-Pro-Phe), which was released by action of trypsin or pepsin and chymotrypsin.

Release of opioid peptides, gluten exorphins by the action of pancreatic elastase.

The release of opioid peptides, gluten exorphins A, which have been isolated from the pepsin-thermolysin digest of wheat gluten, with gastrointestinal proteases was examined. High levels of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr) immunoreactive materials were detected in the pepsin-pancreatic elastase digest by a competitive ELISA. From this digest, gluten exorphin A5, B5 and B4 were isolated. This means that these peptides are released in the gastrointestinal tracts after ingestion of wheat gluten. The yield of gluten exorphin A5 in the pepsin-elastase digest was larger than that in the pepsin-thermolysin digest. The gluten exorphin A5 sequence is found 15 times in the primary structure of the high molecular weight glutenin. The region from which gluten exorphin A5 was released by the action of pancreatic elastase was identified using synthetic fragment peptides.