gastrin-releasing-peptide and Chronic-Disease

Astrocytes are the most abundant glial cells in the central nervous system (CNS), including the spinal cord. Neuronal damage induces astrocytes to become reactive and contribute to various CNS pathologies. Recent studies have demonstrated that astrocytes in the spinal dorsal horn (SDH) become reactive in a transcription factor signal transducer and activator of transcription 3-dependent manner without neuronal damage under chronic itch conditions, causing release of the factor lipocalin-2, leading to induction of sensitization of gastrin releasing peptide-induced chemical itch signaling in the SDH. In this review, we describe recent advances in our understanding of SDH neuronal pathways for itch transmission, the mechanisms of SDH astrocytic activation and its contribution to abnormal itch processing and discuss the role of reactive astrocytes in the SDH in abnormal sensory processing under chronic itch conditions.

Topics: Astrocytes; Chronic Disease; Gastrin-Releasing Peptide; Humans; Lipocalin-2; Neural Pathways; Pruritus; Signal Transduction; Spinal Cord Dorsal Horn; STAT3 Transcription Factor

Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission.. We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations.. Patch-clamp recordings from enhanced green fluorescent protein (EGFP)-expressing (GRPR. We observed potentiation of GRP-evoked excitation in the GRPR. Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR

Topics: Animals; Astrocytes; Chronic Disease; Disease Models, Animal; Gastrin-Releasing Peptide; Male; Mice; Mice, Transgenic; Posterior Horn Cells; Pruritus; Receptors, Bombesin; Signal Transduction

Spinal cord injury (SCI) causes sexual dysfunction, including anejaculation in men. Likewise, chronic mid-thoracic contusion injury impairs ejaculatory reflexes in male rats. Ejaculation is controlled by a spinal ejaculation generator (SEG) comprised of a population of lumbar spinothalamic (LSt) neurons. LSt neurons co-express four neuropeptides, including gastrin-releasing peptide (GRP) and galanin and control ejaculation via release of these peptides in lumbar and sacral autonomic and motor nuclei. Here, we tested the hypothesis that contusion injury causes a disruption of the neuropeptides that are expressed in LSt cell bodies and axon terminals, thereby causing ejaculatory dysfunction. Male Sprague Dawley rats received contusion or sham surgery at spinal levels T6-7. Five to six weeks later, animals were perfused and spinal cords were immunoprocessed for galanin and GRP. Results showed that numbers of cells immunoreactive for galanin were not altered by SCI, suggesting that LSt cells are not ablated by SCI. In contrast, GRP immunoreactivity was decreased in LSt cells following SCI, evidenced by fewer GRP and galanin/GRP dual labeled cells. However, SCI did not affect efferent connections of LSt, cells as axon terminals containing galanin or GRP in contact with autonomic cells were not reduced following SCI. Finally, no changes in testosterone plasma levels or androgen receptor expression were noted after SCI. In conclusion, chronic contusion injury decreased immunoreactivity for GRP in LSt cell soma, but did not affect LSt neurons per se or LSt connections within the SEG. Since GRP is essential for triggering ejaculation, such loss may contribute to ejaculatory dysfunction following SCI.

Topics: Animals; Chronic Disease; Ejaculation; Gastrin-Releasing Peptide; Locomotion; Male; Rats; Rats, Sprague-Dawley; Sexual Dysfunction, Physiological; Spinal Cord Injuries; Thoracic Vertebrae

There are substantial disagreements about the expression of gastrin-releasing peptide (GRP) in sensory neurons and whether GRP antibody cross-reacts with substance P (SP). These concerns necessitate a critical revaluation of GRP expression using additional approaches. Here, we show that a widely used GRP antibody specifically recognizes GRP but not SP. In the spinal cord of mice lacking SP (Tac1KO), the expression of not only GRP but also other peptides, notably neuropeptide Y (NPY), is significantly diminished. We detectedGrpmRNA in dorsal root ganglias using reverse transcription polymerase chain reaction, in situ hybridization and RNA-seq. We demonstrated thatGrpmRNA and protein are upregulated in dorsal root ganglias, but not in the spinal cord, of mice with chronic itch. Few GRP(+)immunostaining signals were detected in spinal sections following dorsal rhizotomy and GRP(+)cell bodies were not detected in dissociated dorsal horn neurons. Ultrastructural analysis further shows that substantially more GRPergic fibers form synaptic contacts with gastrin releasing peptide receptor-positive (GRPR(+)) neurons than SPergic fibers. Our comprehensive study demonstrates that a majority of GRPergic fibers are of primary afferent origin. A number of factors such as low copy number ofGrptranscripts, small percentage of cells expressingGrp, and the use of an eGFP GENSAT transgenic as a surrogate for GRP protein have contributed to the controversy. Optimization of experimental procedures facilitates the specific detection of GRP expression in dorsal root ganglia neurons.

Topics: Amino Acid Sequence; Animals; Antibody Specificity; Cell Count; Cells, Cultured; Chronic Disease; Ganglia, Spinal; Gastrin-Releasing Peptide; Gene Deletion; Gene Expression Regulation; Male; Mice, Inbred C57BL; Mice, Knockout; Posterior Horn Cells; Pruritus; Receptors, Bombesin; RNA, Messenger; Spinal Cord; Substance P

Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.

Topics: Acute-Phase Proteins; Animals; Astrocytes; Chronic Disease; Gastrin-Releasing Peptide; Lipocalin-2; Lipocalins; Male; Mice; Mice, Inbred C57BL; Oncogene Proteins; Pruritus; Spinal Cord Dorsal Horn; STAT3 Transcription Factor

Topics: Animals; Chronic Disease; Disease Models, Animal; Female; Gastrin-Releasing Peptide; Macaca fascicularis; Nerve Fibers; Pruritus; Receptors, Bombesin; Skin; Spinal Cord

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF(Nav1.8) mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.

Topics: Animals; Chronic Disease; Disease Models, Animal; Gastrin-Releasing Peptide; Gene Expression; Humans; MAP Kinase Signaling System; Mice; Mice, Knockout; Mice, Transgenic; NAV1.8 Voltage-Gated Sodium Channel; Nociceptors; Proto-Oncogene Proteins B-raf; Pruritus; Receptors, Bombesin; Receptors, G-Protein-Coupled; Sensory Receptor Cells; Spinal Cord; TRPV Cation Channels

It is not clear whether there is any association between metaplasia of the bronchial epithelium and changes in the distribution of neuroendocrine cells. This study examined, by immunohistological techniques, the distribution of neuroendocrine cells and juxtamucoscal nerve fibres in bronchial biopsies showing metaplastic changes.. Bronchial biopsies from 12 subjects with epithelial metaplasia associated with bronchiectasis and diffuse pulmonary fibrosis were examined by conventional light microscopy and immunohistological techniques for protein gene product 9.5 (PGP), chromogranin A and B (CAB), serotonin, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin releasing peptide (GRP).. Regions of non-metaplastic epithelium contained numerous PGP and serotonin immunoreactive cells. Sub-populations of these cells displayed CAB, CGRP, CT, and GRP immunoreactivity. Metaplastic epithelium contained only a few weakly stained PGP, serotonin, CAB, GRP, CT and CGRP immunoreactive cells in six cases. Metaplastic epithelium was characterised by a high number of CAB-containing cells in six cases and in these biopsies prominent PGP-containing nerve bundles were seen in the subepithelial layer beneath the metaplastic epithelium.. The distribution patterns of neuroendocrine cells and neuronal elements vary between areas of normal and metaplastic epithelium and within areas of metaplastic epithelium. Neuronal hyperplasia was associated with an increase in the number of CAB-containing cells within the metaplastic epithelium.

Topics: Adult; Aged; Bronchi; Calcitonin; Calcitonin Gene-Related Peptide; Chromogranin A; Chromogranins; Chronic Disease; Gastrin-Releasing Peptide; Gastrins; Humans; Immunohistochemistry; Lung Diseases; Middle Aged; Mucous Membrane; Neurosecretory Systems; Peptides; Serotonin; Substance P; Thiolester Hydrolases; Ubiquitin Thiolesterase

The distribution and concentration of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and gastrin-releasing peptide (GRP) immunoreactivities in the pancreas of cats with experimentally induced chronic pancreatitis and of age- and sex-matched controls were investigated. By narrowing the main pancreatic duct between the head and the body to approximately 25% of its normal diameter, we induced within 5 weeks chronic pancreatitis restricted to the body and tail. In control animals, peptide immunoreactive nerves were distributed to the islets, acini, and ducts; the latter were predominantly innervated by fibers immunoreactive for NPY, VIP, or CGRP. The vasculature received an abundant supply of NPY-, CGRP-, and, to a lesser extent, SP-containing axons. Within intrapancreatic ganglia, peptide immunoreactivities were identified in fibers and ganglion cells, with the exception of CGRP and SP immunostaining, which could be visualized only in fibers. In animals with chronic pancreatitis, the innervation pattern of each peptidergic system was comparable to that described in controls. However, there was a remarkable increase in the density and staining intensity of VIP and NPY immunoreactive fibers in the exocrine parenchyma and fibrous septa of the body and tail, where chronic pancreatitis developed. Fibers immunoreactive for CGRP and SP also were moderately denser than in controls, whereas those containing GRP immunoreactivity did not show any detectable changes. In addition, a marked increase of the immunostaining for VIP and, to a much lesser extent, for NPY and GRP, was observed in neurites supplying the head of the pancreas, which appeared devoid of histologically detectable pathological alterations. Radioimmunoassay analysis confirmed the immunohistochemical observations. The increased density of distinct peptidergic nerves in the pancreas with induced chronic pancreatitis might be the result of compensatory phenomena in response to the inflammatory process.

Topics: Animals; Calcitonin Gene-Related Peptide; Cats; Chronic Disease; Constriction; Female; Gastrin-Releasing Peptide; Immunohistochemistry; Male; Neuropeptide Y; Neuropeptides; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Gastrin releasing peptide (GRP) is known to stimulate pancreatic enzyme and islet hormone secretion. In the present immunohistochemical study, the localization and distribution of GRP-like immunoreactivity were investigated in the human pancreas using two antisera with different specificities. GRP-like immunoreactivity (GRP-LI) was observed in numerous nerve fibers diffusely distributed to the exocrine pancreas, but was not seen in intrapancreatic nerve cells of normal pancreatic specimens examined. Nerve fibers and terminals with GRP-LI were found in abundance around pancreatic acini and capillaries, with moderate density around ductules and in the walls of arterioles, and a few were seen in islets. This distribution pattern was quite similar to that of vasoactive intestinal polypeptide (VIP)-LI nerve fibers. The study, using the antibody elution method, strongly suggests the co-localization of GRP- and VIP-LIs within a part of VIP-containing nerve fibers. In the chronic pancreatitis specimens, neurons with GRP-LI were frequently found, and > 90% of intrapancreatic nerve cells were VIP-immunoreactive. Immunostainings for GRP and for VIP on serial adjacent sections of intrapancreatic ganglia from chronic pancreatitis specimens suggested the co-localization of the two immunoreactivities in > 70% of intrapancreatic neurons. The present findings may provide a morphological basis for neurotransmitter and/or neuromodulator roles of GRP in the human pancreas.

Topics: Antibody Specificity; Bombesin; Chronic Disease; Gastrin-Releasing Peptide; Humans; Immunoenzyme Techniques; Nerve Fibers; Neurons; Neuropeptides; Pancreas; Pancreatitis; Peptides; Reference Values; Vasoactive Intestinal Peptide

Bombesin-related peptides (BRP), a family of neuropeptides showing carboxy-terminal homology with the amphibian bombesin, are present in humans in many body systems (CNS, lung, gastro-intestinal tract) with a variety of biological activities. In the lung, BRP are mitogens for normal bronchial epithelial cells and fibroblasts, chemoattractant for monocytes and exert bronchoconstrictive activity. Increased levels of BRP have been described in the lung of cigarette smokers and in smoking-related diseases. Moreover appreciable quantities of BRP have been recently found in lysates of peripheral monocytes and alveolar macrophages of man and guinea pig. It has therefore been inferred that these peptides may play a role in the immunological function of lung tissue. The aim of this study was to determine the amount of BRP present in peripheral-blood mononuclear cells (PBMNC), monocytes and alveolar macrophages (AM) of normal subjects (n = 36) and chronic bronchitis patients (n = 36). Patients with chronic bronchitis showed a significant increase in BRP levels in all cell types (PBMNC, monocytes and AM) (p < 0.005) in comparison with normal subjects. In addition levels of BRP in monocytes and AM were found to be nearly four times higher than in PBMNC in both groups of subjects. We can therefore confirm previous observations concerning the presence of BRP in human cells of the monocyte-macrophage lineage. Furthermore our results demonstrate that BRP levels are increased in monocytes of chronic bronchitis patients and imply a potential role for these neuropeptides in lung immunological response in smoking-related diseases.

Topics: Aged; Bombesin; Bronchitis; Bronchoalveolar Lavage Fluid; Cell Adhesion; Centrifugation, Density Gradient; Chronic Disease; Female; Gastrin-Releasing Peptide; Humans; Leukocytes, Mononuclear; Macrophages, Alveolar; Male; Middle Aged; Monocytes; Peptides; Radioimmunoassay; Reference Values

A rôle for pulmonary endocrine cells has been suggested in the response of the lungs to hypoxia, the control of the pulmonary vasculature and inflammatory pulmonary disease. Since hypoxia, inflammation and vascular remodelling are all central to the pathology of chronic bronchitis and emphysema, we have studied these cells in the lungs of subjects with this condition. In comparison with lungs of matched controls, there was a modest uniform increase in endocrine cells containing gastrin-releasing peptide, possibly associated with vascular remodelling, and a marked increase in cells containing calcitonin, which was particularly seen in consolidated lobes and possibly related to inflammation.

Topics: Aged; Bronchitis; Calcitonin; Chronic Disease; Emphysema; Gastrin-Releasing Peptide; Humans; Immunoenzyme Techniques; Lung; Peptides