Deproceptin

OBJECTIVE: The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal (GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D).

A chimeric opioid peptide (MCRT, YPFPFRTic-NH(2)) was here designed and synthesized. This peptide was based on morphiceptin (YPFP-NH(2)) and a neuropeptide FF (NPFF) derivative (PFRTic-NH(2)) sharing one proline. This peptide is intended to produce potent analgesia. MCRT was found to induce analgesic activity in a dose- and time-dependent manner, as indicated by a tail flick latency test in mice to which it had been intracerebroventricularly administered (5-60 min, 0.025-2.5 nmol/kg (0.5-50 pmol per mouse), ED(50)=1.49 nmol/kg). At 2.5nmol/kg, MCRT showed significantly higher levels of analgesic activity than morphiceptin or PFR(Tic)amide at 2500 nmol/kg. Naltrindole and cyprodime were found to partially but significantly inhibit this analgesic activity, but naloxone blocked it completely. The kappa opioid receptor antagonist nor-BNI was found to slightly inhibit MCRT and morphiceptin. Pre-injection of BIBP3226 and co-administration of NPFF and MCRT showed that NPFF receptors were involved in the analgesia of MCRT.

Matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) regulate proteolysis of the extracellular matrix (ECM) and as a consequence are involved in a number of physiological and pathological states, including cancer. A crucial feature of cancer progression and metastasis is the disruption of the ECM and spreading of proliferating cancer cells. Over-expression of MMPs and uPA is common for most types of cancers and correlates well with the adverse prognosis. Compounds able to modulate the activity of these proteolytic enzymes may become important agents in cancer therapy. In the present study, we examined the effect of the mu-opioid receptor selective peptide, morphiceptin, and its two synthetic analogs on mRNA and protein levels of MMP-9 and uPA in three human cancer cell lines: MCF-7, HT-29, and SH-SY5Y. Our findings indicate that in all three cell lines morphiceptin and its analogs attenuated MMP-9 expression and secretion and that this effect is not mediated by opioid receptors but is under control of the nitric oxide system.

MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.