Biomedical subjects

L E Goehler

Publications and source records attributed to L E Goehler.

34 records · Page 2Linked to original sources

PubMed1995

Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia.

Activation of immune cells by pathogens induces the release of a variety of proinflammatory cytokines, including IL-1 beta and TNF-alpha. Previous studies using IL-1 beta have demonstrated that this cytokine can alter brain function, resulting in a variety of 'illness responses' including increased sleep, decreased food intake, fever, etc. We have recently demonstrated that i.p. IL-1 beta also produces hyperalgesia and that this hyperalgesia (as well as most illness responses) is mediated via activation of subdiaphragmatic vagal afferents. The present series of studies were designed to provide an initial examination of the generality of proinflammatory cytokine-induced hyperalgesia by examining the effects of i.p. TNF-alpha on pain responsivity. These studies demonstrate that: (a) i.p. TNF-alpha produces dose-dependent hyperalgesia as measured by the tailflick test, (b) this hyperalgesia is mediated via the induced release of IL-1 beta, (c) hyperalgesia is mediated via activation of subdiaphragmatic vagal afferents, and (d) the effects of subdiaphragmatic vagotomy cannot be explained by a generalized depression of neural excitability.

Animals↗

PubMed1995

Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are cytokines released by activated immune cells. IL-1 beta and TNF-alpha elicit various illness symptoms including avoidance of novel tastes with which they have been paired (conditioned taste aversion). Previous hypotheses to account for these actions have focused on blood-borne IL-1 beta and TNF-alpha exerting their effects directly at the brain. However, recent evidence suggests that these cytokines may activate subdiaphragmatic vagal afferents. The present experiments demonstrate that subdiaphragmatic vagal transection both attenuates acquisition and facilitates extinction of conditioned taste aversions induced by i.p. administration of either IL-1 beta or TNF-alpha.

Animals↗

PubMed1995

Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication.

Interleukin-1 beta (IL-1 beta), a cytokine released by activated immune cells, elicits various illness symptoms including hyperthermia. Previous hypotheses to account for these actions have focused on blood-borne IL-1 beta exerting its effects directly at the level of the brain. However, recent behavioral and physiological evidence suggest that IL-1 beta can activate the subdiaphragmatic vagus. The present experiments demonstrate that subdiaphragmatic vagal transection disrupts the hyperthermia-inducing effects of recombinant human IL-1 beta and stress. These data provide evidence for a novel route of immune-brain communication, as well as a novel route whereby stress can influence physiological processes.

Animals↗

PubMed1995

Cytokine-to-brain communication: a review & analysis of alternative mechanisms.

It is becoming well accepted that products of the immune system (cytokines) can signal the brain that infection has occurred. This cytokine-to-brain communication can result in marked alterations in brain function and behavior. This review examines alternative mechanisms that have been proposed to explain how such immune products can reach the brain via the blood to cause centrally-mediated "illness" responses. Finally, we describe a new view which argues that cytokines signal brain in quite a different manner, by stimulating afferent terminals of peripheral nerves at local sites of synthesis and release.

Afferent Pathways↗

PubMed1995

Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated.

Processes occurring within the immune system can alter neural function. Cytokines released by cells of the immune system during illness are key messengers in immune-to-brain communication. Interleukin-1 beta (IL-1 beta) is particularly important in this regard and is known to stimulate a myriad of illness-related outcomes such as fever, sickness behavior, aphagia, adipsia, hypothalamic-pituitary-adrenal activation, and changes in pain reactivity. Thus peripherally released IL-1 beta has potent neural effects and is a critical mediator of the impact of immune processes on brain. There is, however, uncertainty concerning the communication pathways involved. We provide evidence that a primary route of peripheral cytokine signalling is through stimulation of peripheral vagal afferents rather than or in addition to direct cytokine access to brain. Subdiaphragmatic, but not hepatic vagotomy, blocked rhIL-1 beta-induced hypothalamic norepinephrine depletion and attenuated rhIL-1 beta-induced increases in serum corticosterone. These data suggest that rhIL-1 beta activates the hypothalamic-pituitary-adrenal axis via stimulation of peripheral vagal afferents and further support the hypothesis that peripheral cytokine signalling to the CNS is mediated primarily by stimulation of peripheral afferents.

Animals↗

PubMed1994

Characterization of cytokine-induced hyperalgesia.

Agents which induce symptoms of illness, such as lipopolysaccharide (LPS), cause diverse effects including hyperalgesia. While previous studies have examined central pathways mediating LPS hyperalgesia, the initial steps in activating this system remain unknown. Since LPS induces the release of various cytokines and eicosinoids from immune cells, the present series of experiments examined the potential involvement of these substances in LPS hyperalgesia. This work demonstrates that: (a) Interleukin-1 beta (IL-1 beta) can produce hyperalgesia following either intraperitoneal or intracerebroventricular injection. In contrast, IL-1 beta delivered intrathecally did not affect pain responsivity. (b) Liver macrophages (Kupffer cells) appear to be critically involved, and relay signals to the brain via hepatic vagal afferents. (c) Both IL-1 beta and tumor necrosis factor appear to be critical mediators of LPS hyperalgesia. In contrast, prostaglandins do not appear to be involved. Taken together, these studies suggest that substances classically thought of as products of the immune system may dynamically enhance pain responsivity via actions either on the hepatic vagus or at central sites.

Animals↗

PubMed1994

Neurocircuitry of illness-induced hyperalgesia.

We have previously demonstrated that illness-inducing agents such as lithium chloride (LiCl) and the bacterial cell wall endotoxin lipopolysaccharide (LPS) produce hyperalgesia on diverse pain measures. The present series of studies attempted to identify the neurocircuitry mediating these effects. These studies have demonstrated that illness-inducing agents produce hyperalgesia by activating: (a) peripheral nerves rather than by generating a blood-borne mediator (Expt. 1); (b) vagal afferents, specifically afferents within the hepatic branch of the vagus (Expt. 2); (c) as yet unidentified brain site(s) rostral to the mid-mesencephalon (Expt. 6); (d) a centrifugal pathway that arises from the nucleus raphe magnus, and not from the adjacent nucleus reticularis paragigantocellularis pars alpha (Expts. 4 and 5); (e) a centrifugal pathway in the dorsolateral funiculus of the spinal cord (Expt. 3); and (f) the same centrifugal pathways for diverse illness inducing agents (Expts. 3, 7 and 8). These data call for the re-evaluation of a number of assumptions inherent in previous studies of hyperalgesia.

Animals↗

PubMed1992

Functional organization of vagal reflex systems in the brain stem of the goldfish, Carassius auratus.

The coordination of secretory and motor responses to food within the alimentary canal requires well organized brain stem reflex systems. In the goldfish, Carassius auratus, three vagal reflex systems control three phases of ingestion and digestion. The orobranchial system sorts food from substrate, the pharyngeal chewing organ prepares items deemed to be food for digestion and absorption, and the abdominal system regulates the digestion of food. Each system is represented in the central nervous system by separate sensory and motor nuclei. The aim of the present study was to determine whether the interrelationships among the vagal sensory and motor nuclei reflect the peripheral organization. The sensory nucleus of each vagal system was injected with the neuronal tracer horseradish peroxidase (HRP), in separate cases. HRP injections into the vagal lobe sensory layers (orobranchial system) labeled fibers projecting topographically to the vagal lobe motor layer, but not at all to the pharyngeal or abdominal motor nuclei. Similarly, injections of HRP into the pharyngeal and abdominal sensory nuclei selectively labeled nerve fibers projecting to the pharyngeal and abdominal motor nuclei, respectively. All injections resulted in labeled fibers and/or cells in the lateral reticular formation, and in fibers ascending in the secondary gustatory-visceral tract. Gustatory information from the pharynx is apparently processed in the same brain stem system as pharyngeal general visceral information, suggesting that functional or regional characteristics of visceral sensory information may be more important for brain stem processing than the traditional "special" (gustatory) versus "general" visceral dichotomy. These results indicate that anatomically and functionally separate reflex systems exist within the goldfish vagal visceral nuclei.

Abdomen↗

PubMed1991

Neuropeptide Y immunoreactivity in the mammalian liver: pattern of innervation and coexistence with tyrosine hydroxylase immunoreactivity.

The distribution of nerve fibers displaying neuropeptide Y immunoreactivity in relationship to the catecholaminergic innervation of rat, guinea pig, and rabbit liver was investigated by single- and double-label immunofluorescence methods. In all three species, neuropeptide Y-immunoreactive fibers are prominent in association with the vasculature, biliary pathway, and stromal compartment. The neuropeptide Y innervation of the parenchyma, on the other hand, differs among the three species in term of density. It is quite sparse in the rat and rabbit, particularly in the former species. In the guinea pig liver, numerous single, varicose neuropeptide Y-containing nerve fibers innervate the hepatic parenchyma; often, thin processes surround single hepatocytes and lie close to sinusoids. The immunoreactive pattern of tyrosine hydroxylase, a marker for catecholaminergic neurons and fibers, is comparable to that of neuropeptide Y. Most neuropeptide Y-containing nerve fibers also contain tyrosine hydroxylase immunoreactivity, in all three species, with the exception of the rabbit parenchyma, where a substantial proportion of catecholaminergic fibers lack immunoreactivity for neuropeptide Y. Finally, systemic administration of the sympathetic neurotoxin, 6-hydroxydopamine, in rats and guinea pigs resulted in virtually complete elimination of both neuropeptide Y- and tyrosine hydroxylase-immunoreactive fibers. These findings are consistent with the hypothesis that neuropeptide Y-containing nerve fibers form a subpopulation of the sympathetic innervation of the mammalian liver, which is likely to originate from prevertebral sympathetic ganglia.

Animals↗

PubMed1988

Calcitonin gene-related peptide immunoreactivity in the biliary pathway and liver of the guinea-pig: distribution and colocalization with substance P.

Calcitonin gene-related peptide immunoreactivity was localized immunohistochemically in nerve fibers innervating the biliary pathway and liver of the guinea-pig. Immunoreactive fibers are present in all layers of the gallbladder and biliary tract and are particularly numerous around blood vessels. In the liver, immunoreactive processes are usually restricted to the interlobular space and porta hepatis, and only a few, very thin, beaded processes were observed in the hepatic parenchyma. A rich innervation is also associated with the vena portae. Positive ganglion cell bodies were not visualized within the ganglionated plexus of the biliary system, whereas they were found in the myenteric and submucosal plexus in the cranial portion of the duodenum corresponding to the sphincter of Oddi. The vast majority, if not all, of calcitonin gene-related peptide-immunoreactive fibers contain substance P immunoreactivity; however, there are some substance P-containing fibers lacking calcitonin gene-related peptide immunoreactivity. The lack of co-occurrence of calcitonin gene-related peptide and substance P immunoreactivities in intrinsic ganglion cells suggests that these two peptides are coexpressed in the extrinsic component of the innervation of the hepatobiliary system.

Animals↗

PubMed1985

Tumor growth in rats: conditioned suppression of food intake and preference.

Rats with experimental tumors developed strong aversions to a novel diet they consumed during tumor growth. Aversions were not evident when the food available during tumor growth was familiar laboratory chow. The impact of learned food aversions on tumor anorexia was evidenced by more severe and long-lasting hypophagia in tumor-bearing animals maintained on a novel diet than in those maintained on laboratory chow. Thus, when a diet is a salient target for the development of learned aversions, the aversions that develop to it can make substantial contributions to the overall syndrome of tumor anorexia. In addition, frequent changes of the diet offered to tumor-bearing rats was associated with milder anorexia than that produced by maintaining tumor-bearing rats on a constant diet. Apparently, the prevention of learned food aversions, or the repeated replacement of aversive foods, can minimize the impact of learned food aversions and attenuate anorexia in tumor-bearing animals.

Animals↗

PubMed1984

Learned aversions to proteins in rats on a dietary self-selection regimen.

Rats were allowed continuous access to protein and carbohydrate macronutrient sources during a sequence of cyclophosphamide (Cytoxan) injections. Significant aversions developed to the protein but not the carbohydrate source in three studies in which the composition of both protein and carbohydrate diets was varied. These results suggest that animals on a dietary self-selection regimen are more likely to develop conditioned aversions to the protein source than the carbohydrate source. In a final study, the generality of these findings was examined by determining whether aversions would selectively arise to protein but not carbohydrate when these nutrients were conditioned in a single trial, with a meal-feeding paradigm. Proteins again proved more salient targets for aversions than carbohydrates. These findings suggest that the tendency to associate proteins with drug-induced illness more readily than carbohydrates is not limited to a self-selection regimen. The possible role of taste factors and/or postingestive effects as the basis of the differential conditioning of proteins and carbohydrates is discussed.

Animals↗

PubMed1983

Relative potency of foods and drinks as targets in aversion conditioning.

The potency of food stimuli as targets in aversion learning was examined using an interference paradigm. In the first study, foods interfered with liquid aversions but liquids did not interfere with food aversions. In the second study, food aversions were found to be resistant to interference by other foods. These findings suggest that foods are relatively potent targets in aversion conditioning in that they are resistant to interference by both foods and drinks. The final study examined the contribution of flavor intensity and nutrient density to the potency of aversion conditioning. The relative potency of foods over drinks may reflect differences in their intensity as well as their different roles in toxin avoidance and nutrient selection.

Animals↗

PubMed1983

Chronic lithium chloride infusions: conditioned suppression of food intake and preference.

A modified learned food aversion paradigm simulated the prolonged food and illness exposure likely to characterize nutrient deficiencies or tumor growth. In this paradigm, a continuously available food was associated with a slow, continuous infusion of LiCl provided by osmotic minipump. Significant aversions were acquired when the available diet was novel but not when it was familiar. Effects of drug infusions on daily food intake were found to parallel those on aversion formation. Marked, persistent suppression of food intake was seen in drug-treated animals consuming a novel diet, but only transient declines were seen in those with a familiar diet. By separating the direct from the conditioned effects on food intake of chronic drug infusions, these studies provided strong evidence that learned food aversions can lead to anorexia.

Animals↗

PubMed1983

Vagotomy produces learned food aversions in the rat.

Subdiaphragmatic vagotomy produces hypophagia and weight loss in normal rats and can reverse the hyperphagia and obesity of rats with ventromedial hypothalamic lesions. Vagotomy surgery can also produce symptoms of nausea and discomfort. Since such symptoms are highly effective as unconditioned stimuli in food aversion conditioning, the present studies examined whether some of the depression in food intake observed in rats with vagotomy could be due to the development of aversions to the foods eaten after their surgery. In the first study, significant aversions developed to the specific novel diet consumed after vagotomy, results indicating that the symptoms associated with vagotomy can serve as effective unconditioned stimuli in the acquisition of learned food aversions. The second study compared vagotomized animals consuming familiar laboratory chow with those consuming a novel diet. In contrast to the novel diets, learned aversions did not develop to the familiar chow, and hypophagia was less persistent and severe. It is concluded that learned food aversions can contribute to the appetite and weight loss exhibited by vagotomized animals. Consideration of the conditions under which these aversions arise after vagotomy surgery may allow for the design of studies so as to minimize the aversions and thereby separate these nonspecific effects from direct regulatory deficits produced by vagotomy.

Animals↗

PubMedDate not supplied

Bacterial endotoxin induces fos immunoreactivity in primary afferent neurons of the vagus nerve.

Subdiaphragmatic vagotomy inhibits brain-mediated illness responses to peripherally administered bacterial endotoxin, including fever, hyperalgesia, sickness behavior, and activation of the hypothalamic-pituitary-adrenal axis. However, direct evidence implicating vagal afferents specifically in conveying information about peripheral immune activation to the brain is still lacking. This study assessed whether (1) endotoxin induces the expression of the functional activation marker Fos in the vagal sensory ganglia, and (2) vagotomy abrogates endotoxin-induced Fos expression in these ganglia. Male rats, which had previously received vagotomy or sham surgery, were injected intraperitoneally or intravenously with either endotoxin or saline. Fos immunolabeling was absent in saline-treated rats. In contrast, scattered cells within the vagal sensory ganglia showed Fos immunoreactivity after both intraperitoneal and intravenous endotoxin administration in sham-operated rats. Vagotomy abolished Fos expression after intraperitoneal endotoxin administration, whereas after intravenous administration Fos expression was strongly attenuated, but not eliminated. These findings implicate vagal afferents as a potential signaling pathway to brain regions that generate illness responses to pro-inflammatory mediators.

Animals↗