This confirmatory work is aimed to test that the hypothesis that the gastrin releasing peptide (GRP) receptor - the BB2 receptor - is necessary for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by the small and the large forms of GRP in the rat, GRP-10 and GRP-29, and to confirm the sites of action regulating such responses - the vascular bed of the celiac artery (CA, supplying stomach and upper duodenum). To pursue these aims we measured first MS and IMI length in response to GRP-10 and GRP-29 (0, 0.5nmol/kg) infused in the CA (n=8 rats) and the cranial mesenteric artery (CMA, supplying the small and part of the large intestine, n=8 rats) in near spontaneously free feeding rats pretreated with the BB2 receptor antagonist BW2258U89 (0.1mg/kg) in the same arteries prior to the onset of the dark cycle. We found that GRP-29, but not GRP-10, infused by the CA reduced MS and prolonged the IMI by decreasing meal latency and meal duration and the BB2 receptor antagonist BW2258U89 infused in the same artery attenuated these responses. These results suggest that the BB2 receptor is necessary for reduction of MS and prolongation of the IMI by exogenous GRP-29, and the vascular bed of the CA, stomach and upper duodenum, contains sites of action regulating these feeding responses.

01 Jul 2010·European Journal of PharmacologyQ3 · MEDICINE

Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells

Q3 · MEDICINE

Article

Author: Terry W. Moody ; Robert T. Jensen ; Marc J. Berna ; Veronica Sancho ; Lisa Ridnour ; David A. Wink ; Daniel Chan ; Giuseppe Giaccone ; Samuel Mantey

Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr(1068) of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)alpha antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.

16 Nov 2006·PsychopharmacologyQ3 · MEDICINE

The role of gastrin-releasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat

Q3 · MEDICINE

Article

Author: Christine Mountney ; Zul Merali ; Pam Kent ; Victoria Sillberg ; Hymie Anisman

RATIONALEBombesin (BB), an amphibian peptide, was shown to affect the expression of the stress response. However, the physiological role of the mammalian counterparts of BB in mediating anxiety and fear responses remain to be characterized.OBJECTIVEThis study examined the effects of gastrin-releasing peptide (GRP), a mammalian analogue of BB, and its receptor antagonist, BW2258U89, on conditioned emotional response (CER), using fear conditioning.MATERIALS AND METHODSThe effects of these compounds on contextual and cued fear conditioning were assessed after direct bilateral infusions into the prelimbic (PrL) cortex, infralimbic (IL) cortex or central nucleus of the amygdala (CeA).RESULTSGRP (300 ng) microinjected into each of the three target nuclei significantly reduced freezing to contextual cues. Similarly, in the cued portion of CER, GRP administered to the IL cortex significantly reduced freezing. Administration of BW2258U89 resulted in dose-dependent and site-specific effects. At the IL cortex, the 50 ng dose decreased freezing to both contextual and cued fear conditioning. At the CeA, the 300 ng dose also decreased freezing, but at the 50 ng dose, it increased contextual freezing. At the PrL cortex, BW2258U89 did not affect freezing.CONCLUSIONSThese results illustrate that (1) GRP system(s) can significantly affect the expression of learned fear, (2) some of the relevant brain sites mediating these effects include the PrL, IL and the CeA, and (3) such effects may be dependent upon whether responses were evoked by environmental contextual fear cues or by specific auditory cues that were explicitly paired with an aversive stimulus.

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Indication	Highest Phase	Country/Location	Organization	Date
Small Cell Lung Cancer	Phase 2	US	Burroughs Wellcome	-

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