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Central somatostatin receptor 1 activation reverses acute stress-related alterations of gastric and colonic motor function in mice.

ABSTRACT: Corticotropin-releasing factor (CRF) signaling induced by stress is well established to delay gastric emptying (GE) and stimulate colonic functions. The somatostatin receptor (sst(1-5) ) agonist, ODT8-SST acts in the brain to inhibit stress-induced adrenocorticotropic hormone and epinephrine secretion. We investigated whether ODT8-SST acts in the brain to influence stress-related alterations of gastric and colonic motor function and sst receptor subtype(s) involved.Peptides were injected intracerebroventricularly (i.c.v.) under short isoflurane anesthesia and GE, fecal pellet output (FPO) and distal colonic motility monitored in conscious mice.The stress of acute anesthesia/vehicle i.c.v. injection reduced GE by 67% and increased defecation by 99% compared to non-injected controls. Both responses were abolished by ODT8-SST (1?g= 0.75nmol) or sst(1) agonist (0.65-1.95nmol). The sst(1) agonist (1.95nmol) also prevented the abdominal surgery-induced delayed GE. Octreotide (sst(2) ?>sst(5) ?> sst(3) ) and the sst(2) or sst(4) agonists (1?g=0.78 or 0.70nmol, respectively) injected i.c.v. did not influence FPO while i.c.v. somatostatin-28 mimicked ODT8-SST's effect. The ODT8-SST-induced increased food intake was inhibited by i.c.v. sst(2) antagonist while the reduced FPO was unchanged. ODT8-SST i.c.v. reduced distal colonic motility in semi-restrained mice compared with vehicle and blocked water avoidance- and i.c.v. CRF (0.5?g=0.09nmol)-induced stimulated FPO while a similar colonic secretomotor response to i.p. 5-hydroxytryptophane (10mgkg(-1) =36.4?mol?kg(-1) ) was unaltered. Conclusions & Inferences? ODT8-SST counteracts stress/i.c.v. CRF-related stimulation of colonic motor function and delayed GE which can be reproduced mainly by activation of sst(1) receptors. These data opens new insight to brain somatostatinergic signaling pathways interfering with brain circuitries involved in gut motor responses to acute stress.

SUBMITTER: Stengel A

PROVIDER: S-EPMC3683311 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Central somatostatin receptor 1 activation reverses acute stress-related alterations of gastric and colonic motor function in mice.

Stengel A A Goebel-Stengel M M Wang L L Larauche M M Rivier J J Taché Y Y

Neurogastroenterology and motility 20110601 6

<h4>Background</h4>Corticotropin-releasing factor (CRF) signaling induced by stress is well established to delay gastric emptying (GE) and stimulate colonic functions. The somatostatin receptor (sst(1-5) ) agonist, ODT8-SST acts in the brain to inhibit stress-induced adrenocorticotropic hormone and epinephrine secretion. We investigated whether ODT8-SST acts in the brain to influence stress-related alterations of gastric and colonic motor function and sst receptor subtype(s) involved.<h4>Methods ...[more]

PMID: 21564422

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Project description:Corticotropin-releasing factor receptor-1 (CRF(1)) mediates the stress-induced colonic motor activity. Less is known about the role of CRF(2) in the colonic response to stress.We studied colonic contractile activity in rats and CRF(2)-/-, CRF-overexpressing, and wild-type mice using still manometry; we analyzed defecation induced by acute partial-restraint stress (PRS), and/or intraperitoneal injection of CRF ligands. In rats, we monitored activation of the colonic longitudinal muscle myenteric plexus (LMMP) neurons and localization of CRF(1) and CRF(2) using immunohistochemical and immunoblot analyses. We measured phosphorylation of extracellular signal-regulated kinase 1/2 by CRF ligands in primary cultures of LMMP neurons (PC-LMMPn) and cyclic adenosine monophosphate (cAMP) production in human embryonic kidney-293 cells transfected with CRF(1) and/or CRF(2).In rats, a selective agonist of CRF(2) (urocortin 2) reduced CRF-induced defecation (>50%), colonic contractile activity, and Fos expression in the colonic LMMP. A selective antagonist of CRF(2) (astressin(2)-B) increased these responses. Urocortin 2 reduced PRS-induced colonic contractile activity in wild-type and CRF-overexpressing mice, whereas disruption of CRF(2) increased PRS-induced colonic contractile activity and CRF-induced defecation. CRF(2) colocalized with CRF(1) and neuronal nitric oxide synthase in the rat colon, LMMP, and PC-LMMPn. CRF-induced phosphorylation of extracellular signal-regulated kinase in PC-LMMPn; this was inhibited or increased by a selective antagonist of CRF(1) (NBI35965) or astressin(2)-B, respectively. The half maximal effective concentration, EC(50), for the CRF-induced cAMP response was 8.6 nmol/L in human embryonic kidney-293 cells that express only CRF(1); this response was suppressed 10-fold in cells that express CRF(1) and CRF(2).In colon tissues of rodents, CRF(2) activation inhibits CRF(1) signaling in myenteric neurons and the stress-induced colonic motor responses. Disruption of CRF(2) function impairs colonic coping responses to stress.

Project description:Acute central nervous system injuries are among the most common causes of disability worldwide, with widespread social and economic implications. Motor tract injury accounts for the majority of this disability; therefore, there is impetus to understand mechanisms underlying the pathophysiology of injury and subsequent reorganization of the motor tract that may lead to recovery. After acute central nervous system injury, there are changes in the microenvironment and structure of the motor tract. For example, ischemic stroke involves decreased local blood flow and tissue death from lack of oxygen and nutrients. Traumatic injury, in contrast, causes stretching and shearing injury to microstructures, including myelinated axons and their surrounding vessels. Both involve blood-brain barrier dysfunction, which is an important initial event. After acute central nervous system injury, motor tract reorganization occurs in the form of cortical remapping in the gray matter and axonal regeneration and rewiring in the white matter. Cortical remapping involves one cortical region taking on the role of another. cAMP-response-element binding protein is a key transcription factor that can enhance plasticity in the peri-infarct cortex. Axonal regeneration and rewiring depend on complex cell-cell interactions between axons, oligodendrocytes, and other cells. The RhoA/Rho-associated coiled-coil containing kinase signaling pathway plays a central role in axon growth/regeneration through interactions with myelin-derived axonal growth inhibitors and regulation of actin cytoskeletal dynamics. Oligodendrocytes and their precursors play a role in myelination, and neurons are involved through their voltage-gated calcium channels. Understanding the pathophysiology of injury and the biology of motor tract reorganization may allow the development of therapies to enhance recovery after acute central nervous system injury. These include targeted rehabilitation, novel pharmacotherapies, such as growth factors and axonal growth inhibitor blockade, and the implementation of neurotechnologies, such as central nervous system stimulators and robotics. The translation of these advances depends on careful alignment of preclinical studies and human clinical trials. As experimental data mount, the future is one of optimism.

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Central somatostatin receptor 1 activation reverses acute stress-related alterations of gastric and colonic motor function in mice.

Publications

Central somatostatin receptor 1 activation reverses acute stress-related alterations of gastric and colonic motor function in mice.

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