Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species-dependent migration in lung adenocarcinoma cells.

Nerve fibers and neurotransmitters have increasingly been shown to have a role in tumor progression. Gastrin-releasing peptide is a neuropeptide linked to tumor aggressiveness, acting as an autocrine tumor growth factor by binding to its receptor, gastrin-releasing peptide receptor, expressed by many tumors. Although neuropeptides have been previously linked to tumor cell proliferation, more recent studies have uncovered roles for neuropeptides in chemotaxis and metastasis. Understanding the precise roles of such peptides in cancer is crucial to optimizing targeted therapy design. We have previously described that gastrin-releasing peptide acts directly as a chemotactic factor for neutrophils, dependent on PI3K, ERK, and p38. In this study, we investigated roles for gastrin-releasing peptide in lung adenocarcinoma. We asked if gastrin-releasing peptide would act as a proliferative and/or chemotactic stimulus for gastrin-releasing peptide receptor-expressing tumor cells. In A549 cells, a non-small cell lung carcinoma line, the treatment with gastrin-releasing peptide leads to activation of AKT and ERK1/2, and production of reactive oxygen species. Gastrin-releasing peptide induced migration of A549 cells, dependent on gastrin-releasing peptide receptor and PI3K, but not ERK. However, no proliferation was observed in these cells in response to gastrin-releasing peptide, and gastrin-releasing peptide did not promote resistance to treatment with a chemotherapy drug. Our results suggest that, similar to what happens in neutrophils, gastrin-releasing peptide is a migratory, rather than a proliferative, stimulus, for non-small cell lung carcinoma cells, indicating a putative role for gastrin-releasing peptide and gastrin-releasing peptide receptor in metastasis.

Infusion of exogenous cholecystokinin-8, gastrin releasing peptide-29 and their combination reduce body weight in diet-induced obese male rats.

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.

Roux-en-Y gastric bypass augments the feeding responses evoked by gastrin-releasing peptides.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most effective method for the treatment of obesity, and metabolic disease RYGB may reduce body weight by altering the feeding responses evoked by the short-term satiety peptides. MATERIALS AND METHODS: Here, we measured meal size (MS, chow), intermeal interval (IMI) length, and satiety ratio (SR, IMI/MS; food consumed per a unit of time) by the small and the large forms of gastrin-releasing peptide (GRP) in rats, GRP-10 and GRP-29 (0, 0.1, 0.5 nmol/kg) infused in the celiac artery (CA, supplies stomach and upper duodenum) and the cranial mesenteric artery (CMA, supplies small and large intestine) in an RYGB rat model. RESULTS: GRP-10 reduced MS, prolonged the IMI, and increased the SR only in the RYGB group, whereas GRP-29 evoked these responses by both routes and in both groups. CONCLUSIONS: The RYGB procedure augments the feeding responses evoked by exogenous GRP, possibly by decreasing total food intake, increasing latency to the first meal, decreasing number of meals or altering the sites of action regulating MS and IMI length by the two peptides.

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils.

Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-ß2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

Elucidating the roles of gut neuropeptides on channel catfish feed intake, glycemia, and hypothalamic NPY and POMC expression.

Both intrinsic and extrinsic factors modulate food intake and glycemia in vertebrates, in part through interactions with hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons. The objective of this project was to elucidate the effects of ghrelin (GHRL), gastrin-releasing peptide (GRP), cholecystokinin (CCK), glucagon-like peptide (GLP), pancreatic polypeptide (PP), and peptide YY (PYY) on appetite, glycemia, and hypothalamic expression of NPY and POMC in channel catfish. Catfish were injected intraperitoneally with a single peptide at concentrations of either 0 (control), 50, 100, or 200 ng/g body weight (BW), respectively. Fish were allowed to recover for 30 min, and then fed to satiation over 1 h. Feed intake was determined 1h post-feeding. Catfish injected with GHRL at 50 and 100 ng/g BW and GRP at 200 ng/g BW consumed significantly (P<0.05) less feed compared to controls. A tendency (P<0.1) to suppress feed intake was also observed in the 200 ng/g BW GHRL and PP treatments. PYY, CCK, and GLP had no effects on feed intake. Glycemia was not affected by GHRL, GRP, PP, and PYY treatments, but was suppressed by CCK. A tendency toward lower plasma glucose concentrations was observed in fish administered GLP at 50 ng/g BW. Hypothalamic NPY expression was highly variable and not significantly affected by treatment. POMC expression was also variable, but tended to be reduced by the highest concentration of CCK. These results provide new insight into the roles and regulation of gut neuropeptides in catfish appetite and glycemia.

Exogenously administered bombesin and gastrin releasing peptide contract the female rat urethra in vivo and in vitro.

BACKGROUND: Bombesin (BOM) and gastrin releasing peptide (GRP) have been located to the lower urinary tract (LUT). However, there is a paucity of data demonstrating the impact of these endogenous peptides. OBJECTIVES: The aim of the present study was to investigate the contractile actions of BOM and GRP on the female rat urethra in vitro and in vivo. Female Sprague-Dawley rats (n = 37) weighing approximately 225 g were used. Intraurethral pressure was recorded by a catheter placed at the maximum pressure zone corresponding to the intrinsic urethral sphincter. MEASUREMENTS: In vitro, changes in intraurethral pressure was conducted on perfused intact urethral/bladder preparations and are expressed as percentages of sphincteric intraurethral pressure achieved with noradrenaline. In vivo, changes in intraurethral pressure was conducted in anesthetized subjects and compared with the baseline intraurethral pressure and sham controls. RESULTS: In vitro, the increase in intraurethral pressure induced by BOM was 23.6 ± 3.2 cmH(2)O, exceeding the pressure evoked with NA by 9.6 cmH(2) O or 174.4% whereas GRP induced a maximum pressure of 10.7 ± 1.6 cmH(2) O, an increase of 2.2 ± 0.5 cmH(2) O or 82.9% (P < 0.05) of the NA evoked pressure. In vivo, the mean baseline pressure was 22.9 ± 1.4 cmH(2) O. The intraurethral pressure evoked by BOM was 50.6 ± 6.3 cmH(2) O (P < 0.05), and for GRP, the evoked intraurethral pressure was 56.2 ± 13.4 cmH(2) O (P < 0.05). CONCLUSIONS: The present data suggest that both BOM and GRP may contribute to the control of continence by their contractile action on the sphincters of the LUT outflow region.

Exogenously administered bombesin and gastrin releasing peptide contract the female rat urethra in vivo and in vitro.

BACKGROUND: Bombesin (BOM) and gastrin releasing peptide (GRP) have been located to the lower urinary tract. However, there is a paucity of data demonstrating the impact of these neuropeptides. OBJECTIVES: The present study investigates the impact of BOM and GRP in the female Sprague-Dawley rats 225 g b.w. n = 37 urethras in vitro and in vivo. Intraurethral pressure was recorded by a catheter placed at the maximum pressure zone corresponding to the intrinsic urethral spincter. MEASUREMENTS: In vitro, the intraurethral pressure was measured in response to the administration of BOM and GRP and noradrenaline from perfused intact urethral/bladder preparations. In vivo, changes in intraurethral pressure were conducted in anesthetized subjects and compared with the basal intraurethral pressure and sham controls. RESULTS: In vitro, the increase in intraurethral pressure induced by BOM was 23.6 ± 3.2 cmH(2) O, exceeding the pressure evoked with NA by 10.7 cmH(2) O whereas GRP induced 10.7 ± 1.6 cmH(2) O, an increase of 3.3 cmH(2) O but less than the NA evoked intraurethral pressure by 2.2 cmH(2) O. Incubation with scopolamine (1 µM), phentolamine (1 µM), pancuronium (1 µM), and indomethacin (1 µM) did not produce any significant difference in the contractile responses to BOM or GRP. In vivo, the mean basal pressure was 22.9 ± 1.4 cmH(2) O. The intraurethral pressure evoked by BOM was 29.7 cmH(2) O (21.3 ± 1.3 to 51.0 ± 1.6 cmH(2) O), and for GRP, the evoked intraurethral pressure was 33.8 cmH(2) O (22.3 ± 1.9 to 56.2 ± 30 cmH(2) O). CONCLUSIONS: BOM and GRP may contribute to the control of continence by their contractile action on the sphincters of the lower urinary tract outflow region.

Feeding and drinking response following central administrations of bombesin-like peptides in chicks.

Gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been isolated as homologues of bombesin. Central administration of bombesin inhibits feeding behavior in chicks (Gallus gallus) while the effects of GRP and NMB have not been reported. The purpose of the present study was to investigate whether intracerebroventricular (ICV) injection of GRP, NMB and neuromedin C (NMC, the C-terminus decapeptide of GRP) affected feeding and drinking behavior in chicks. Injection of GRP, NMC and NMB (0.2-5 nmol) decreased feeding behavior in chicks while drinking behavior was not affected. ICV injection of 5 nmol GRP and NMC decreased voluntary locomotion while NMB did not. It is therefore possible that GRP- and NMC-associated hypoactivity is related to the peptides' anorexigenic effects. GRP, NMC and NMB did not affect plasma corticosterone concentration, suggesting that hypothalamus-pituitary-adrenal axis might not be related to the anorexigenic action of these peptides. All these findings support the hypothesis that GRP, NMC and NMB function as anorexigenic factors in the brain of chicks.

Gastrin releasing peptide-induced satiety is associated with hypothalamic and brainstem changes in chicks.

Gastrin releasing peptide (GRP) is involved in the stimulation of gastric acid release from the stomach. It also mediates effects on feeding behavior. It is associated with anorexigenic effects in both mammalian and avian species, but the mechanism of action is unknown in any species. The aim of the present study was thus to investigate the hypothalamic and brainstem mechanisms mediating GRP-induced satiety in chicks. In Experiment 1, chicks that received intracerebroventricular (ICV) injection of GRP reduced food intake for up to 150 min following injection and reduced water intake up to 120 min following injection. In Experiment 2, chicks that were food restricted following GRP injection did not reduce water intake. Alimentary canal transit time was not affected by GRP in Experiment 3. A behavior analysis was conducted in Experiment 4, revealing that GRP-treated chicks reduced feeding pecks. In Experiment 5, GRP-treated chicks had increased c-Fos immunoreactivity in the lateral hypothalamus, paraventricular nucleus, and arcuate nucleus of the hypothalamus, and the nucleus of the solitary tract. Collectively, these results demonstrate that central GRP causes anorexigenic effects that are associated with hypothalamic changes without affecting other behaviors.

Effects of gastrin-releasing peptide agonist and antagonist administered to the basolateral nucleus of the amygdala on conditioned fear in the rat.

RATIONALE: Bombesin (BB)-like peptides have been shown to affect neuroendocrine and neural functions related to the stress response and the modulation of conditioned fear. In line with this view, central administration of gastrin-releasing peptide (GRP; a mammalian analogue of BB) or its receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) BB(6-14) (RC-3095) modulates conditioned fear. OBJECTIVE: The present study examined the effects of bilateral infusions of GRP or its receptor antagonist (RC-3095) into the basolateral nucleus of the amygdala (BLA) on the conditioned emotional response. METHODS: The effects of GRP (150, 300, and 600 ng/0.5 microl) and/or RC-3095 (50, 500, and 1,000 ng/0.5 microl) on contextual and cued fear conditioning were assessed following direct bilateral infusion of these compounds into the BLA. RESULTS: Both GRP and RC-3095 (all doses) reduced freezing during the contextual testing period but did not influence responding in the cued test. Although both compounds reduced freezing in the contextual paradigms, at a moderate dose pretreatment with RC-3095 attenuated the GRP-elicited decrease in contextual freezing. CONCLUSIONS: It appears that manipulation of GRP at the BLA may influence the expression of learned fear and that these effects preferentially influence contextual versus cue-dependent emotional responses.

A Placebo-Controlled Crossover Trial of Gastrin-Releasing Peptide in Childhood Autism.

OBJECTIVES: The aim of this study was to evaluate the efficacy, safety, and tolerability of gastrin-releasing peptide (GRP) compared with placebo in autism spectrum disorder symptoms. METHODOLOGY: This is a randomized, double-blind, placebo-controlled crossover trial using GRP 160 pmol/kg for 4 consecutive days in 10 children with autism. Outcomes were measured by the Aberrant Behavior Checklist (ABC) scale. RESULTS: All participants were boys, aged between 4 and 9 years. There was a reduction in the scores of the ABC range and its subscales after use GRP and placebo. The reduction was more prominent with GRP, particularly in the subscale "hyperactivity and noncompliance," but there was no statistical difference between the results (P = 0.334). After a week of infusion, 5 children showed improvement of 25% or greater in the total score of the ABC scale with GRP use and 2 with placebo use; however, there was no statistical difference (P = 0.375). There were no adverse effects, changes in vital signs, or laboratory abnormalities associated with the use of GRP. CONCLUSIONS: The results of this study, despite the small sample size, reinforce previous data on the safety of the GRP in short-term use. There is a need for further research with other designs and a larger sample size to evaluate the efficacy and safety of GRP in children with autism.

Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.

Signaling within the master clock of the brain: localized activation of mitogen-activated protein kinase by gastrin-releasing peptide.

The circadian clock located in the mammalian suprachiasmatic nucleus (SCN) exhibits substantial heterogeneity in both its neurochemical and functional organization, with retinal input and oscillatory timekeeping functions segregated to different regions within the nucleus. Although it is clear that photic information must be relayed from directly retinorecipient cells to the population of oscillator cells within the nucleus, the intra-SCN signal (or signals) underlying such communication has yet to be identified. Gastrin-releasing peptide (GRP), which is found within calbindin-containing retinorecipient cells and causes photic-like phase shifts when applied directly to the SCN, is a candidate molecule. Here we examine the effect of GRP on both molecular and behavioral properties of the hamster circadian system. Within 30 min a third ventricle injection of GRP produces an increase in the number of cells expressing the phosphorylated form of extracellular signal-regulated kinases 1/2 (p-ERK1/2), localized in a discrete group of SCN cells that form a cap dorsal to calbindin cells and lateral to vasopressin cells. At 1 h after the peak of p-ERK expression these cap cells express c-fos, Period1, and Period2. Pharmacological blockade of ERK phosphorylation attenuates phase shifts to GRP. These data indicate that GRP is an output signal of retinorecipient SCN cells and activates a small cluster of SCN neurons. This novel cell group likely serves as a relay or integration point for communicating photic phase-resetting information to the rhythmic cells of the SCN. These findings represent a first step in deconstructing the SCN network constituting the brain clock.

Improvement of autism spectrum disorder symptoms in three children by using gastrin-releasing peptide.

OBJECTIVE: To evaluate the safety, tolerability and potential therapeutic effects of gastrin-releasing peptide in three children with autistic spectrum disorder. METHODS: Case series study with the intravenous administration of gastrin-releasing peptide in the dose of 160pmol/kg for four consecutive days. To evaluate the results, parental impressions the Childhood Autism Rating Scale (CARS) and the Clinical Global Impression (CGI) Scale. Each child underwent a new peptide cycle after two weeks. The children were followed for four weeks after the end of the infusions. RESULTS: The gastrin-releasing peptide was well tolerated and no child had adverse effects. Two children had improved social interaction, with a slight improvement in joint attention and the interaction initiatives. Two showed reduction of stereotypes and improvement in verbal language. One child lost his compulsion to bathe, an effect that lasted two weeks after each infusion cycle. Average reduction in CARS score was 2.8 points. CGI was "minimally better" in two children and "much better" in one. CONCLUSIONS: This study suggests that the gastrin-releasing peptide is safe and may be effective in improving key symptoms of autism spectrum disorder, but its results should be interpreted with caution. Controlled clinical trials-randomized, double-blinded, and with more children-are needed to better evaluate the possible therapeutic effects of gastrin-releasing peptide in autism.

Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.

The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 µg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 µg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 µg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 µg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels.

Electrophysiological properties of brain-natriuretic peptide- and gastrin-releasing peptide-responsive dorsal horn neurons in spinal itch transmission.

Spinal itch transmission has been reported to be mediated by at least two neuronal populations in spinal dorsal horn, neurons expressing brain-natriuretic peptide (BNP) receptor (Npra) and gastrin-releasing peptide (GRP) receptor (GRPR). Although Npra-expressing neurons were shown to be upstream of GRPR- expressing neurons in spinal itch transmission, the roles of BNP and GRP in the spinal neurotransmission of histamine-dependent and -independent itch remains unclear. Using in vivo electrophysiology and behavior analysis, this study examined the responses of chloroquine (histamine-independent pruritogen)-responsive and histamine-responsive dorsal horn neurons to spinal applications of BNP and GRP. Electrophysiologically, 9.5% of chloroquine-responsive neurons responded to BNP, 33.3% to GRP, and 4.8% to both, indicating that almost half of chloroquine-responsive neurons were unresponsive to both BNP and GRP. In contrast, histamine-responsive neurons did not respond to spinal BNP application, whereas 30% responded to spinal GRP application, indicating that 70% of histamine-responsive neurons were unresponsive to both BNP and GRP. Behavioral analyses showed differences in the time-course and frequency of scratching responses evoked by intrathecal BNP and GRP. These findings provide evidence that most BNP-Npra and GRP-GRPR signaling involve different pathways of spinal itch transmission, and that multiple neurotransmitters, in addition to BNP and GRP, are involved in spinal itch transmission. The electrophysiological results also suggest that spinal BNP contributes little to histaminergic itch directly.

Targeting prostate cancer cells with genetically engineered polypeptide-based micelles displaying gastrin-releasing peptide.

In recent years G protein-coupled receptors (GPCRs) have emerged as crucial tumorigenic factors that drive aberrant cancer growth, metastasis and angiogenesis. Consequently, a number of GPCRs are strongly expressed in cancer derived cell lines and tissue samples. Therefore a rational anti-cancer strategy is the design of nano-medicines that specifically target GPCRs to bind and internalise cytotoxic drugs into cancer cells. Herein, we report the genetic engineering of a self-assembling nanoparticle based on elastin-like polypeptide (ELP), which has been fused with gastrin releasing peptide (GRP). These nanoparticles increased intracellular calcium concentrations when added to GRP receptor positive PC-3 prostate cancer cells, demonstrating specific receptor activation. Moreover, GRP-displaying fluorescent labelled nanoparticles showed specific cell-surface interaction with PC-3 prostate cancer cells and increased endocytic uptake. These nanoparticles therefore provide a targeted molecular carrier system for evaluating the delivery of cytotoxic drugs into cancer cells.

Mechanisms underlying anorexia after microinjection of bombesin into the lateral cerebroventricle.

Intracerebroventricular (i.c.v.) injections of bombesin (BN) and gastrin-releasing peptide (GRP) dose-dependently decreased food intake in male Wistar rats fasted for 17 h. Neuromedin B (NMB) did not show any effect on food intake. After BN administration, locomotor activity did not significantly change, compared with a vehicle-injected group. The anorexia induced by BN (0.3 microg) was perfectly inhibited by pretreatment with a GRP-receptor antagonist, [D-Tyr(6)]BN(6-13) methyl ester (10 microg), an NO synthase inhibitor, L-nitro-arginine (30 microg), and a PKG inhibitor, H-9 (2 microg). The cGMP concentration in the hypothalamus increased 1 h after administration when compared with the vehicle-injected group. On the other hand, an NMB-receptor antagonist, BIM23127 (10 microg), and the protein kinase (PK) C inhibitors, chelerythrine (2 microg) and Go6983 (2 microg), inhibited only the late phase of the anorexia. A PKC activator, phorbol 12, 13-dibutyrate (3 microg), injected into the ventricle decreased food intake. These findings suggest that BN suppresses food intake mainly mediated through the GRP receptor and NO-cGMP-PKG pathway, and NMB receptor and PKC is partly involved in the late phase of the anorexia.

Effects of central gastrin-releasing peptide on glucose metabolism.

Gastrin-releasing peptide (GRP) mediated signals in the central nervous system (CNS) influence many functions associated with energy metabolism. The purpose of the present study was to investigate the central effect of GRP on glucose metabolism in the male rat. Intracerebroventricular (icv) administration of GRP caused an immediate hyperglycaemia which was sustained till the end of the infusion. The rise in plasma glucose levels was accompanied by an increase in endogenous glucose production (EGP), as well as increases in plasma glucagon and insulin concentrations. Furthermore, no differences in plasma corticosterone levels were noted between control and GRP treated rats. These results demonstrate that central GRP increases plasma glucose levels, probably by stimulating pancreatic glucagon release and concomitantly or subsequently endogenous glucose production.

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates.

How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, ß-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike ß-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both ß-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by ß-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.