Neurohumoral Pathways Research Articles

Comparative localization of leucine-rich repeat-containing G-protein-coupled receptor-7 (RXFP1) mRNA and [33P]-relaxin binding sites in rat brain: Restricted somatic co-expression a clue to relaxin action?

Relaxin is a polypeptide hormone with established actions associated with reproductive physiology, but until recently the precise nature of the relaxin receptor and its transmembrane signaling mechanisms had remained elusive. In 2002 however, the leucine-rich-repeat-containing G-protein-coupled receptor-7 (now classified as RXFP1) was identified as a cognate receptor for relaxin, with activation resulting in stimulation of intracellular cAMP production. These findings, along with the presence and putative actions of relaxin within the CNS and earlier descriptions of relaxin binding sites in brain, suggest the importance and feasibility of determining if these relaxin binding sites represent leucine-rich-repeat-containing G-protein-coupled receptor-7 and their precise comparative distribution. Thus, the current study reports the distribution of leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA throughout the rat brain using in situ hybridization histochemistry of [35S]-labeled oligonucleotides and the comparative distribution of [33P]-human relaxin binding sites. The extensive, topographical distribution of leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA throughout the adult rat brain correlated very closely to that of [33P]-relaxin binding sites. Leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA was expressed by neurons in several brain regions, including the olfactory bulb, cerebral cortex, thalamus, hippocampus, hypothalamus, midbrain, pons and medulla. Receptor transcripts were most abundant in areas such as the basolateral amygdala, subiculum, deep layers of the cingulate, somatosensory and motor cortices and intralaminar/midline thalamic nuclei. These areas also contained very high densities of [33P]-relaxin binding sites, suggesting a largely somatic localization of leucine-rich-repeat-containing G-protein-coupled receptor-7 protein and site of action for relaxin peptide. The central distribution of relaxin-producing neurons has been described, while data on the topography of nerve terminals that contain and secrete the peptide are currently lacking; but overall these findings strongly suggest that leucine-rich-repeat-containing G-protein-coupled receptor-7 is the cognate receptor for relaxin in the rat brain, and support a role for relaxin-leucine-rich-repeat-containing G-protein-coupled receptor-7 signaling in various somatosensory, autonomic and neurohumoral pathways, which warrants further investigation.

Neurohumoral Pathways in Heart Failure With Preserved Systolic Function

Other than natriuretic peptides, neurohumoral markers have not been studied adequately in heart failure with preserved systolic function. There is little evidence of chronic activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, as in heart failure with reduced systolic function. These and other neurohumoral pathways may, however, become excessively stimulated by exercise and during episodes of acute decompensation. Blood natriuretic peptide concentrations are chronically elevated in patients with heart failure and preserved systolic function but not to the same extent as in patients with reduced systolic function. The role of neurohumoral antagonists in the treatment of heart failure and preserved systolic function has yet to be fully investigated.

Effects of Systolic Atrial Function on Plasma Renin Activity and Natriuretic Peptide Secretion after High Rate Atrial and Ventricular Pacing in Dogs

Rapid atrial rates cause electrical, structural remodeling, and neuro-humoral changes. This study compares the effects of mechanical remodeling on plasma renin activity (PRA) and atrial natriuretic peptide (ANP) secretion. Eight beagles were subjected to rapid atrial pacing (AP) at 400 beats/min for 16 days. After complete recovery of left ventricular function, they underwent rapid ventricular pacing (VP) at 240 beats/min of equal duration. Left atrial systolic maximal dimension (LAmax) and left atrial appendage (LAA) peak late emptying velocity (LAA-E) were assessed by echocardiography. Blood samples were taken from the right atrium and from the peripheral vein. LAmax after AP and VP enlarged significantly (2.16 +/- 0.21 cm vs 2.41 +/- 0.23 cm, P = 0.002). Compared with baseline, LAA-E velocities were significantly reduced (0.65 +/- 0.12 m/s vs 0.26 +/- 0.16 m/s, P = 0.001) after AP only. AP caused a significant elevation of PRA in right atrial (9.28 +/- 4.23 nmol/L per hour) and peripheral samples compared with baseline values (4.82 +/- 2.53 nmol/L per hour, P = 0.04). ANP levels increased after AP (1117.12 +/- 252.21 fmol/L) with respect to baseline values (824.37 +/- 159.08 fmol/L, P = 0.001). There was no difference in PRA and ANP levels between atrial and peripheral samples. Atrial size and impaired systolic appendage function play an important role in secretion of PRA and ANP. Both neuro-humoral pathways may be therapeutic targets in the treatment of patients with AF.

Increased peripheral resistance in heart failure: new evidence suggests an alteration in vascular smooth muscle function.

Increased peripheral resistance is a hallmark of chronic heart failure and has been primarily attributed to neurohumoral pathways involving both the renin-angiotensin and sympathetic nervous systems. The increased resistance is thought to serve as a compensatory mechanism to help maintain perfusion to the vital organs by sustaining blood pressure in the fate of a failing heart. Local mechanisms, and in particular endothelial dysfunction, have also been shown to be important contributors in regulating arterial resistance and vascular remodeling in this disease. In this issue of the British Journal of Pharmacology, Gschwend et al. (2003) present new data suggesting that in the absence of a functional endothelium, myogenic constriction of small pressurized mesenteric arteries, an intrinsic property of vascular smooth muscle cells, is enhanced in a coronary artery ligation-induced myocardial infarction model of congestive heart failure (CHF) in the rat. The increased myogenic tone appears to be tightly linked to angiotensin II type 1 receptors (AT(1)). The possibility that CHF-induced stimulation of myogenic constriction is due to the local release of preformed angiotensin II or constitutive upregulation of the AT(1) receptor signaling pathways are discussed along with other potential cellular and molecular mechanisms previously suggested to play a role in myogenic reactivity.

Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice.

Whether left ventricular hypertrophy (LVH) in obesity results from increased hemodynamic load or altered neurohormonal signaling remains controversial. Dysregulation of leptin, a neurohormone essential to energy homeostasis, is implicated in the pathogenesis of obesity. Because leptin has cardiovascular bioactivity, we hypothesized that disruption of leptin signaling mediates the development of obesity-associated LVH. We measured left ventricular (LV) wall thickness and LV mass with echocardiography in mice lacking leptin (ob/ob, n=15) or functional receptor (db/db, n=10) and controls at 2, 4, and 6 months of age. None of the mice had LVH at 2 months. Progressive obesity developed in ob/ob and db/db mice. At 6 months, LVH occurred in ob/ob and db/db compared with controls. We observed corresponding myocyte hypertrophy by light microscopy. To separate the direct contribution of leptin deficiency from mechanical effects of obesity, we induced weight loss in 6- to 8-month-old ob/ob mice either by leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size. Together these data show that the effect of leptin on LV remodeling is not attributable to weight loss alone, indicating that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohumoral pathway. Disruption of leptin signaling may represent a novel mechanism in LVH and related cardiovascular disorders.

Different patterns of angiotensin II and atrial natriuretic peptide secretion in a sheep model of atrial fibrillation.

It is well established that rapid atrial rates, as in atrial fibrillation (AF), cause atrial electrical and structural remodeling leading to the maintenance of AF. The role of neurohumoral changes in this pathophysiologic vicious circle remains unclear. We followed the concentrations of angiotensin II (AT II) and atrial natriuretic peptide (ANP) in a sheep model of AF. The sheep were atrially paced at 600 beats/min for 15 weeks. Electrophysiologic study was performed at regular intervals, and venous blood samples were taken. There was a slow increase in the vulnerability for AF. The cumulative incidence of sustained AF was 80% after 15 weeks of pacing. This increased vulnerability for AF was accompanied by atrial electrical remodeling and an increase in atrial pressure. AT II increased rapidly and stayed elevated: 17+/-4 pg/mL at baseline, and 40+/-11 and 39+/-7 pg/mL after 1 and 12 weeks of pacing, respectively. ANP rose more progressively: 35+/-7 pg/mL at baseline, and 72+/-17, 95+/-10, and 106+/-23 pg/mL after 1, 3, and 12 weeks, respectively. ANP levels correlated with atrial pressure and inducibility of AF. There was no relation between these parameters and AT II levels. AT II and ANP increased significantly in this animal model of AF. Elevation of AT II occurs early and seems to be dependent on rapid atrial rate rather than the presence of AF. ANP increased more progressively. It paralleled the inducibility of AF and atrial stretch. Both neurohumoral pathways may form a potential therapeutic target for treatment of patients with AF.

New and emerging pharmacological strategies in the management of chronic heart failure.

Chronic heart failure is a complex syndrome involving the activation of multiple cellular, metabolic and neurohumoral pathways following the initial myocardial insult. Because of the complexity of the disease, strategies targeting these multiple systems involved in disease progression are required to maximise the therapeutic benefits of intervention. To this end, there are a number of approaches currently under active evaluation. These include the inhibition of additional neurohormonal vasoconstrictor systems (e.g. endothelin and vasopressin systems), cytokine antagonists (e.g. agents that block tumour necrosis factor-alpha activity), agents that favourably modulate extracellular matrix (e.g. matrix metalloprotease inhibitors) and agents that augment natriuretic peptides.

New and emerging pharmacologic strategies in the management of chronic heart failure.

Chronic heart failure (CHF) is a complex syndrome involving activation of multiple cellular, metabolic, and neurohumoral pathways following the initial myocardial insult. Recently, there have been considerable advances in the pharmacologic management of CHF. The current approach to treatment recognizes the need to target neurohormonal activation, and the use of angiotensin-converting enzyme (ACE) inhibitors and beta blockers should now be regarded as part of standard therapy in many patients with CHF. However, because of the complexity of the disease, blockade of additional pathways is likely to be required to maximize the therapeutic benefit of intervention. To this end, there are several agents under active late-phase clinical evaluation. The most advanced of these new strategies (beyond renin-angiotensin-aldosterone blockade) is inhibition of the endothelin system. There is a substantial body of evidence that this system is intimately involved in CHF disease progression. Early-phase clinical data are very encouraging and support the potential utility of long-term endothelin inhibition. Other novel approaches involve the use of cytokine antagonists (e.g., agents that block tumor necrosis factor-alpha activity) and the augmentation of natriuretic peptides. If all these potential agents prove to be of benefit in CHF, the question of which agent or combination of agents to use in which patients will arise. There is therefore a need to develop scientific approaches in order to be able to identify more accurately patients who will obtain benefit from specific classes or combinations of drugs.

Prolonged elevation in blood pressure in the unrestrained rat exposed to chlorpyrifos

Organophosphate (OP) pesticides are likely to alter the regulation of blood pressure (BP) because (i) BP control centers in the brain stem utilize cholinergic synapses and (ii) the irreversible inhibition of acetylcholinesterase activity by OP’s causes cholinergic stimulation in the CNS. This study used radiotelemetric techniques to monitor systolic (S), diastolic (D), mean (M) BP, pulse pressure (systolic–diastolic), heart rate (HR), core temperature ( T c), and motor activity in male Long–Evans rats treated with the OP pesticide chlorpyrifos (CHP) at doses of 0, 5, 10, and 25 mg/kg (p.o.) at 15:00 h 10 and 25 mg/kg CHP led to parallel elevations in S-BP, M-BP, and D-BP within 2 h after dosing. BP increased 15–20 mmHg above controls and increases persisted throughout the night and into the next day. HR decreased slightly in rats administered 25 but not 10 mg/kg CHP. T c was reduced by treatment with 25 mg/kg CHP and then increased above controls the next day. Motor activity was reduced by treatment with 25 but not 10 mg/kg CHP. Pulse pressure was elevated by 2–4 mmHg for 40 h after exposure to 10 and 25 mg/kg CHP. The increase in BP without an increase in HR suggests that CHP increases total peripheral resistance and may alter the baroreflex control of BP. Cholinergic stimulation of the CNS may explain the initial effects of CHP on BP; however, the persistent elevation suggests an involvement of neurohumoral pressor pathways.

MORE THAN A MARKER: INTERACTION BETWEEN THE CIRCADIAN REGULATION OF TEMPERATURE AND SLEEP, AGE-RELATED CHANGES, AND TREATMENT POSSIBILITIES

The neurobiological mechanisms of both sleep and circadianregulation have been unraveled partly in the last decades. A network of brainstructures, rather than a single locus, is involved in arousal state regulation,whereas the suprachiasmatic nucleus (SCN) has been recognized as a key structurefor the regulation of circadian rhythms. Although most models of sleep regulationinclude a circadian component, the actual mechanism by which the circadiantiming system promotes—in addition to homeostatic pressure—transitionsbetween sleep and wakefulness remains to be elucidated. Little more can bestated presently than a probable involvement of neuronal projections and neurohumoralfactors originating in the SCN. This paper reviews the relation among bodytemperature, arousal state, and the circadian timing system and proposes thatthe circadian temperature rhythm provides an additional signaling pathwayfor the circadian modulation of sleep and wakefulness. A review of the literatureshows that increased brain temperature is associated with a type of neuronalactivation typical of sleep in some structures (hypothalamus, basal forebrain),but typical of wakefulness in others (midbrain reticular formation, thalamus).Not only local temperature, but also skin temperature are related to the activationtype in these structures. Warming of the skin is associated with an activationtype typical of sleep in the midbrain reticular formation, hypothalamus, andcerebral cortex (CC). The decreasing part of the circadian rhythm in coretemperature is mainly determined by heat loss from the skin of the extremities,which is associated with strongly increased skin temperature. As such, alterationsin core and skin temperature over the day could modulate the neuronal activationstate or “preparedness for sleep” in arousal-related brain structures.Body temperature may thus provide a third signaling pathway, in addition tosynaptic and neurohumoral pathways, for the circadian modulation of sleep.A proposed model for the effects of body temperature on sleep appears to fitthe available data better than previous hypotheses on the relation betweentemperature and sleep. Moreover, when the effects of age-related thermoregulatoryalterations are introduced into the model, it provides an adequate descriptionof age-related changes in sleep, including shallow sleep and awakening closerto the nocturnal core temperature minimum. Finally, the model indicates thatappropriately timed direct (passive heating) or indirect (bright light, melatonin,physical activity) manipulation of the nocturnal profile of skin and coretemperature may be beneficial to disturbed sleep in the elderly. Althoughsuch procedures could be viewed by researchers as merely masking a markerfor the endogenous rhythm, they may in fact be crucial for sleep improvementin elderly subjects. (Chronobiology International,17(3), 313–354, 2000)

Interconnections between the Neuroendocrine Hypothalamus and the Central Autonomic System: Geoffrey Harris Memorial Lecture, Kitakyushu, Japan, October 1998

Tract-tracing techniques in combination with immunohistochemistry and in situ hybridization were used in intact and operated rats (hypothalamic lesions, transections of neuronal pathways) to localize and characterize neuronal connections between the hypothalamus and autonomic centers. Viscerosensory and somatosensory signals which relay in the spinal cord and the medulla oblongata reach the hypothalamus through various catecholaminergic and noncatecholaminergic neuronal pathways. Vice versa, the hypothalamus influences autonomic activities through humoral and neurohumoral pathways. Descending hypothalamic efferents carry feedback signals to viscerosensory and brainstem catecholaminergic neurons and regulatory inputs to parasympathetic (dorsal vagal nucleus) and sympathetic (thoracolumbar intermediolateral cell column) preganglionic neurons. These fibers arise mainly from neurons of the paraventricular, arcuate, perifornical, and dorsomedial nuclei and the lateral hypothalamus. The major neuroanatomical observations are the following: (1) pathways between the hypothalamus and autonomic centers are bidirectional: the ascending and descending fibers may use the same avenues; (2) the descending axons are mainly peptidergic (CRF, vasopressin, oxytocin, somatostatin, enkephalin, POMC, and cANP), while the ascending fibers are both peptidergic (enkephalin, NPY, neurotensin, dynorphins) and catecholaminergic; (3) descending hypothalamic axons terminate directly on the sensory, preganglionic, and catecholaminergic neurons in the medulla and the spinal cord; (4) hypothalamic projections to the autonomic centers are always bilateral; (5) while medullary autonomic and catecholaminergic fibers innervate hypothalamic neurons directly, spinohypothalamic axons are relayed on neurons in the lateral hypothalamus.

Increased tone of the rectal wall in response to feeding persists in patients with cauda equina syndrome.

The aim was to study fasting and postprandial rectal tone in patients with cauda equina injury. Electromechanical barostat measurement of rectal tone was made in 13 healthy volunteers and in five patients during a 10 min recording, while fasting and for 1 h after a 1000 kCal intake. A prompt decrease of rectal volume was observed in all control subjects and patients. The delay between the end of the meal and the onset of the rectal response was always less than 3 min in the five patients as well as in the control group. The rapidity of the rectal response to feeding observed in our five patients suggests that the rectal response was mediated via a neural or neurohumoral pathway despite severe injury of the sacral parasympathetic supply.

Nicotine and Endogenous Opioids: Toward Specific Pharmacotherapy

To address the theoretical framework behind opioid receptor antagonism for the treatment of nicotine abuse. The current literature is reviewed with a focus on opioid-nicotine interactions in animals and humans. Furthermore, previous studies addressing the effect of opioid antagonism on smoking behaviour are reviewed critically with a focus on suggestions and implications for future trials. Computerized data bases and reference lists of existing articles were searched for prior publications in 3 areas: 1) the association between nicotine and endogenous opioids, 2) nicotine and reward, and 3) opioid antagonism in the treatment of nicotine use. Nicotine affects the mesolimbic reward pathway postsynaptically via nicotinic cholinergic receptors and presynaptically via the central nervous system's (CNS) neurohumoral pathways. Thus nicotine results in the release of endogenous opioids that bind to mu receptors, which increases the release of dopamine along this pathway. Studies to date have shown mixed results on the effect of opioid antagonism on smoking behaviour. The role of opioid antagonism on smoking behaviour is unclear, despite the publication of 5 trials on the subject. Further trials of longer duration should be undertaken and use both longer-acting medications and those more specific to the mu receptor to further focus on the rewarding aspects of nicotine ingestion, thus addressing the craving for this drug. The development of adequate compounds has just begun, and psychiatrists can hope to have a more specific pharmacotherapy to address the cravings and short-term rewards of nicotine use.

The cellular pathophysiology of progression to heart failure.

Congestive heart failure is the final common pathway of diverse etiologies that result in impaired systolic and diastolic function, deleterious activation of neurohumoral pathways, and high morbidity and mortality. Many studies published in 1995 significantly added to our understanding of the pathophysiologies of heart failure at the cellular level. Because a common accompaniment to all forms of low output heart failure are hypertrophy and contractile dysfunction of the cardiomyocyte, applications of the techniques of molecular and cell biology to animal models that demonstrate this phenomenon are providing new insights into the mechanisms responsible for this important clinical problem. In the past year, critical information was derived from animal models that mimic human cardiac hypertrophy and failure. Likewise, genetically engineered mice in which a gene product of interest is overexpressed or eliminated provided critical information, in particular regarding the roles of phospholamban and beta-adrenergic receptor kinase 1 in mediating the contractile responses of the heart to beta-adrenergic stimulation. Furthermore, study of human myocardial tissue from patients with end-stage cardiomyopathy continues to provide insight into the diverse etiologies of heart failure. The recent applications of the techniques of molecular and cell biology to this clinical problem are likely to accelerate our understanding of the complex mechanisms responsible for this syndrome.

Effects of heat stress on vascular capacitance.

In dogs and humans, heat stress is associated with an increase in cardiac output that sustains blood flow to heat-dissipating organs. Because cardiac output and venous return are equal in the steady state, the circulation must also adjust in heat stress to allow the venous return to increase. To analyze these adjustments, we measured blood volumes, unstressed volumes, blood flow distribution, venous compliance, venous resistance, and the time constant of venous drainage of the splanchnic and extrasplanchnic vascular beds in dogs anesthetized with alpha-chloralose at normal and at high core temperatures. We repeated the measurements at high core temperatures with ganglionic blockade, alpha-adrenergic receptor blockade, or beta-adrenergic receptor blockade to determine the efferent neurohumoral pathway. When core temperature was increased from 37.8 +/- 0.2 to 41.9 +/- 0.1 degrees C, total splanchnic blood volume decreased 23% (4.6 +/- 1.4 ml/kg) and splanchnic unstressed volume decreased 38.5%. None of the other determinants of venous return changed. Ganglionic blockade shifted the total and unstressed splanchnic blood volume during heat stress back to normothermic values. However, beta- and alpha-blockade did not affect splanchnic volumes. We conclude that a decrease in splanchnic unstressed volume is an important factor for the increased venous return during heat stress. Although mediated through sympathetic ganglions, this decrease is not abolished by alpha- or beta-receptor blockade.

Hypertension and the brain.

The brain plays an important role in the short-term regulation of blood pressure via sympathetic and parasympathetic mechanisms as well as other neurohumoral pathways including the hypothalamo-pituitary axis. The role of the central nervous system in long-term blood pressure control is less well defined but centrally mediated increased sympathetic activity has been identified in the spontaneously hypertensive rat. In addition to the role of the brain in the control of blood pressure and mechanisms of hypertension, there are important effects of blood pressure on brain function. Hypertension is a major risk factor for cerebrovascular disease and stroke. Effective antihypertensive treatment can reduce the relative risk of stroke by up to 40% and control of blood pressure appears to prevent both atherothrombotic and haemorrhagic stroke.

In vivo monitoring of tissue function and metabolism using positron emission tomography

Positron emission tomography (PET) relies on a combination of the use of positron-emitting radioactive tracers and computerized tomography to monitor certain physiological and functional characteristics in vivo and noninvasively. Its special and most powerful applications to date are in brain physiology and neurology. There are many potential research applications in farm animals, such as the mapping of neuro-humoral pathways, but cost and the need for special facilities are likely to be prohibitive.

Inhibition of Gastric Motor Function by Circulating Corticotropin‐Releasing Factor in Anesthetized Rats

We have investigated the influence of intravenous corticotropin‐releasing factor (CRF) on intraluminal pressure of the body of the stomach and the neurohumoral pathways through which CRF inhibits gastric motor function in rats. CRF (0.21–210 pmol) injected intravenously produced a dose‐dependent, long‐lasting decrease in baseline tone and inhibited phasic gastric contractions measured manometrically in urethane‐anesthetized rats. The inhibitory effect of CRF was abolished by administration of hexamethonium or by subdiaphragmatic vagotomy but was unaffected by perineural treatment of the vagus nerves with capsaicin, adrenalectomy, or celiac/superior mesenteric ganglionectomy. Intravenous administration of CRF (126 pmol) inhibited by 69% the emptying of a noncaloric liquid meal as measured by the phenol red technique in conscious rats. Hexamethonium pretreatment significantly attenuated the CRF ‐induced delay in gastric emptying; bretylium, naloxone, adrenalectomy, and celiac I superior mesenteric ganglionectomy had no such effect. In an isolated tissue preparation, CRF (10−11 to 10−6 M) inhibited spontaneous, but not carbachol‐induced, contractions of rat antral longitudinal muscle. The effect of CRF was dose‐dependent and abolished in the presence of tetrodotoxin. These results suggest that peripheral CRF‐induced inhibition of corpus and antral motor contractility may mediate delayed gastric emptying via an action involving a nicotinic synapse, presumably in the enteric nervous system, that requires a vagal input. The in vitro studies support the concept that the action of CRF is not direct on smooth muscle but involves neural transmission within the enteric nervous system.

Neurohumoral pathways mediating stress-induced inhibition of gastric acid secretion in rats

In awake rats, physical restraint inhibited pentagastrin-stimulated gastric acid secretion by more than 50%. This inhibitory effect was abolished by either ganglionic or noradrenergic blockade. Adrenalectomy, as well as pretreatment with a vasopressin V1-receptor antagonist, significantly attenuated the gastric inhibitory effect in response to stress. In contrast, neither truncal vagotomy nor hypophysectomy or opiate blockade prevented stress-induced inhibition of gastric acid secretion. These findings indicate that stress-induced inhibition of gastric acid secretion in rats is mediated by autonomic, noradrenergic efferents as well as by adrenal and vasopressindependent pathways. Vagal efferents, opiate pathways, and the pituitary gland do not seem to be involved.

Neurohumoral pathways mediating changes in rat gastrointestinal transit

Pharmacologic and surgical procedures were used to define the neurohumoral pathways that mediate stress-induced changes in gastrointestinal transit in the rat. Physical restraint (a validated Stressor) resulted in significant inhibition of gastric emptying and small bowel transit but in stimulation of large bowel transit. Most importantly, the results indicate that stress-induced changes in gastrointestinal transit in rats are differentially mediated by sympathetic and parasympathetic efferents of the autonomic nervous system and, in part, by opiate pathways but not by the pituitary and adrenal glands. Stress-induced inhibition of gastric emptying is mediated by noradrenergic efferents, whereas stress-induced changes in small and large bowel transit are predominantly mediated by vagal, parasympathetic efferents.