Neurocircuitry of illness-induced hyperalgesia

Watkins, Linda R.; Wiertelak, Eric P.; Goehler, Lisa E.; Mooney-Heiberger, K.; Martinez, José A.; Furness, Linda E.; Smith, Kathrine P.; Maier, Steve F.

doi:10.1016/0006-8993(94)91742-6

Cited by 263 publications

(135 citation statements)

References 81 publications

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“…Fos was found in the raphe magnus (Watkins, et al, 1994) and in the dorsal raphe (Turek and Ryabinin, 2005) after hypothermic ip doses of endotoxin greater than 50μg/kg, but not in the raphe pallidus after an iv dose of 5μg/kg (Zhang et al, 2003). The distribution after CLP was restricted to the area shown in Fig.…”

Section: Discussionmentioning

confidence: 82%

“…The administration of bacterial endotoxin has gained wide use as a systemic inflammatory stimulus (Beishuizen and Thijs, 2003;Carlson et al, 1997;Gaykema et al, 1995;Wan et al, 1994;Watkins et al, 1994), but the utility of endotoxin administration as an experimental model of sepsis has been questioned (Mathiak et al, 2000;Wichterman et al, 1980). The central neural responses to acute doses of endotoxin Wan, et al, 1994) or inflammatory cytokines (Chan et al, 1993;Crane et al, 2003;Ericsson et al, 1994;Xu et al, 1999) have been well described and are likely to be present in sepsis but may comprise only a subset of the complete response to prolonged systemic infection.…”

Section: Introductionmentioning

confidence: 99%

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Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Carlson

Chiu

Fiedler

et al. 2007

Experimental Neurology

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Although brain pathways activated by sepsis may respond acutely to endotoxin administration, the long-term central response to sepsis is not known. We prepared male rats for hormonal sampling at the circadian nadir (AM) and peak (PM) after cecal ligation and puncture (CLP) or sham surgery. Diurnal variation of corticosterone was present on postoperative day (D) 3 and D4 after sham surgery but not after CLP. CLP increased Fos immunostaining in the nucleus of tractus solitarius (NTS), ventrolateral medulla, medullary raphe, parabrachial nucleus, hypothalamus, amygdala, bed nucleus of stria terminalis, and preoptic region. Fos responses were generally greatest on D1 but persisted to the AM of D4. The number of Fos-positive cell nuclei in the NTS on D3 and D4 did not differ but had greater variance on D3 than on D4 (P < 0.01) with a divergent response in the PM of D3 that was correlated with plasma ACTH (r = 0.927, P<0.01) but not with corticosterone. CLP increased CRH-staining intensity in the hypothalamic paraventricular neurons uniformly from D1 through D4 (P<0.01). Similar to Fos in NTS, this response was correlated with plasma ACTH (r = 0.738, P<0.05) and adrenal size (r = 0.730, P<0.05) in the PM of D3. Neuronal CRH became detectable after CLP in specific medullary areas on D1 and in the preoptic region on D3 and D4. Thus, the suppression of circadian variation by CLP was associated with central neural responses that increased in relation to plasma ACTH without apparent influence on the release of corticosterone.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Carlson

Chiu

Fiedler

et al. 2007

Experimental Neurology

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“…Initially, it was demonstrated that a subdiaphragmatic vagotomy prevented the cerebral Fos response to ip LPS [129]. Subsequently, several groups demonstrated that vagal lesions could prevent the CNS effects of ip IL-1 or LPS on behavior [130,131]. Subdiaphragmatic vagotomy also attenuated the HPA response to IL-1 and prevented the decreases in hypothalamic NE [20].…”

Section: Mechanisms Of the Neurochemical Effects Of Cytokinesmentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

285

169

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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“…Indeed, circulatory endotoxin causes the release of a wide array of chemical mediators, such as histamine (31), lipoxygenase metabolites (34), nitric oxide (18), and cytokines (17). Recent investigations have suggested that cytokine interleukins are the chemical mediators responsible for activation of abdominal vagal afferents by circulatory endotoxin, thus providing the signaling to elicit several brain-mediated illness responses, including fever (37), hyperalgesia (47), and the activation of the hypothalamic-pituitary-adrenal axis (14). Evidently, stimulation of vagal afferents by endotoxin-related mediators is not unique in the lung.…”

Section: Discussionmentioning

confidence: 99%

The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

Lai

Ruan

Kou

2005

Journal of Applied Physiology

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The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats. J Appl Physiol 98: 620 -628, 2005. First published October 1, 2004; doi:10.1152/japplphysiol.00539.2004.-Circulatory endotoxin can stimulate vagal pulmonary C fibers and rapidly adapting receptors (RARs) in rats, but the underlying mechanisms are not clear. We investigated the involvement of hydroxyl radicals and cyclooxygenase metabolites in the stimulation of C fibers and RARs by circulatory endotoxin (50 mg/kg) in 112 anesthetized, paralyzed, and artificially ventilated rats. In rats pretreated with the vehicle, endotoxin stimulated C fibers and RARs and caused a slight increase in total lung resistance (RL) and a decrease in dynamic lung compliance. In rats pretreated with dimethylthiourea (a hydroxyl radical scavenger) alone, indomethacin (a cyclooxygenase inhibitor) alone, or a combination of the two, C-fiber and RAR responses [C fiber: change (⌬) ϭ Ϫ62, Ϫ79, and Ϫ85%; RAR: ⌬ ϭ Ϫ80, Ϫ84, and Ϫ84%, respectively] were reduced, and the RL response was prevented. The suppressive effects of a combination of dimethylthiourea and indomethacin on the C-fiber and RAR responses were not superior to indomethacin alone. In rats pretreated with isoproterenol (a bronchodilator), the C-fiber response was not significantly affected (⌬ ϭ Ϫ26%), the RAR response was reduced (⌬ ϭ Ϫ88%), and the RL response was prevented. None of these pretreatments affected the dynamic lung compliance response. These results suggest that 1) both hydroxyl radicals and cyclooxygenase metabolites are involved in the endotoxin-induced stimulation of C fibers and RARs, and 2) the involvement of these two metabolites in the C-fiber stimulation may be due to their chemical effects, whereas that in the RAR stimulation may be due to their bronchoconstrictive effects. pulmonary C fibers; rapidly adapting receptors; reactive oxygen metabolites ENDOTOXEMIA CAUSES TACHYPNEA, leading to hyperventilation in septic shock patients (3, 4), but the causes are not completely understood. The tachypnea induced by circulatory endotoxin in rats is prevented by bilateral cervical vagotomy, suggesting that it is a vagally mediated respiratory reflex (42). Electrophysiological studies in rats have revealed that lung C-fiber nerve endings (C fibers) and pulmonary rapidly adapting receptors (RARs), two major types of lung vagal sensory receptors, are activated by circulatory endotoxin (21). Both lung C fibers and RARs play an important role in the detection of pulmonary pathophysiological conditions and eliciting resultant respiratory reflexes (9,25,40). The physiological characteristics of these two types of lung receptors are different (9,25,40). For example, lung C fibers are very sensitive to chemical stimuli (e.g., chemical mediators) but relatively insensitive to mechanical stimuli (e.g., bronchoconstriction). In contrast, RARs can be stimulated by chemical mediators and/or changes in lung mechanics. The mechanisms...

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Neurocircuitry of illness-induced hyperalgesia

Cited by 263 publications

References 81 publications

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Effects of cytokines and infections on brain neurochemistry

The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

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