Prostaglandin E2 enhances the sensitizing effect of hyperthermia on pulmonary C-fibers in rats

Zhang, Guangfan; Lee, Lu-Yuan

doi:10.1016/j.resp.2006.11.003

Cited by 7 publications

(7 citation statements)

References 30 publications

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“…Indeed, Kubista et al showed that cangrelor antagonises the inhibition of neuronal Ca 2+ channels by adenine nucleotides, which is mediated by P2Y 12 and paralleled by inhibition of cAMP accumulation (23). The importance of cAMP in the activation of afferent C-fibers is highlighted by the effect of prostaglandin E 2 (PGE 2 ), which potentiated hyperthermia-induced hypersensitivity of vagal pulmonary C-fibers through its interaction with Gs-coupled EP2 and EP4 receptors (24). Moreover, inhalation of PGE 2 aerosol significantly increased the dyspnoic sensation during exercise in healthy human subjects, without inducing changes in airway resistance or lung volume (25).…”

Section: Hypothesis: Ticagrelor-induced Dyspnea Is Mediated By Inhibimentioning

confidence: 99%

Why does ticagrelor induce dyspnea?

Cattaneo¹,

Faioni²

2012

Thromb Haemost

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SummaryIn studies that compared the reversible P2Y 12 inhibitor ticagrelor with the irreversible inhibitor clopidogrel, dyspnea was observed more frequently among ticagrelor-treated patients than among clopidogreltreated patients. Because dyspnea was not associated with acidosis, pulmonary or cardiac dysfunction, alterations in the mechanisms and pathways of the sensation of dyspnea may be involved in its pathogenesis. It has been hypothesised that the sensation of dyspnea in ticagrelor-treated patients is triggered by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration in the circulation. However, dipyridamole, a much stronger inhibitor of adenosine clearance than ticagrelor, usually does not cause dyspnea. We hypothesise that inhibition of P2Y 12 on sensory neurons increases the sensation of dyspnea, particularly when reversible inhibitors are used. We base our hypothesis on the following considerations: 1) cangrelor and elinogrel, which, like ticagrelor, are reversible P2Y 12 inhibitors, also increase the incidence of dyspnea; 2) it is biologically plausible that inhibition of P2Y 12 on sensory neurons increases the sensation of dyspnea; 3) inhibition of P2Y 12 on platelets (which do not have a nucleus) by clopidogrel is permanent, despite the once daily administration and the short plasma half-life of the inhibitor; 4) in contrast, inhibition of P2Y 12 on neurons by clopidogrel may be temporary and transient, because neurons have a nucleus and can therefore rapidly replace the inhibited receptors with newly synthetised ones; 5) inhibition of P2Y 12 on neurons by reversible inhibitors is permanent, because the plasma drug concentration is maintained high by repeated dosing, in order to ensure permanent inhibition of platelet P2Y 12 .

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Section: Hypothesis: Ticagrelor-induced Dyspnea Is Mediated By Inhibimentioning

confidence: 99%

Why does ticagrelor induce dyspnea?

Cattaneo¹,

Faioni²

2012

Thromb Haemost

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“…For example, a classical pro-nociceptive mediator prostaglandin E 2 sensitizes the vagal C-fiber terminals to physical and chemical stimuli via direct action on the EP2 receptor in their neuronal membrane (Ho et al, 2000; Lee et al, 1995; Zhang et al, 2007). Mechanistically, the PGE 2 –induced sensitization has been attributed to the combination of receptor-specific sensitization (such as TRPV1 sensitization) and an increase in non-specific sensory excitability (Kwong et al, 2002).…”

Section: Putative Vagal Nociceptive Nerve Fibers In the Lungsmentioning

confidence: 99%

Vagal afferent nerves with the properties of nociceptors

Kollárik

Ren

Brozmanová

2010

Autonomic Neuroscience

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Vagal afferent nerves are essential for optimal neural regulation of visceral organs, but are not often considered important for their defense. However, there are well-defined subsets of vagal afferent nerves that have activation properties indicative of specialization to detect potentially harmful stimuli (nociceptors). This is clearly exemplified by the vagal bronchopulmonary C-fibers that are quiescent in healthy lungs but are readily activated by noxious chemicals and inflammatory molecules. Vagal afferent nerves with similar activation properties have been also identified in the esophagus and probably exist in other visceral tissues. In addition, these putative vagal C-fibers often initiate defensive reflexes, can be sensitized, and have the capacity to induce central sensitization. This set of properties is characteristic of nociceptors in somatic tissues.

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“…This surgery results in total subdiaphragmatic vagal denervation, including hepatic afferent vagal denervation, but it does not eliminate supradiaphragmatic (e.g., pulmonary) innervation. Together with the liver, the lungs are the major sources of peripheral PGE 2 synthesis during fever (25,82), and PGE 2 has been shown to affect pulmonary vagal afferents in a receptor-specific manner (95). To eliminate the possibility that supradiaphragmatic vagus could convey febrigenic signals to the brain, we performed experiments with bilateral cervical vagotomy.…”

Section: Intravenous Pge 2 -Induced Fever Can Occur Independently Of mentioning

confidence: 99%

Fever response to intravenous prostaglandin E₂ is mediated by the brain but does not require afferent vagal signaling

Ootsuka¹,

Blessing²,

Steiner³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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PGE2 produced in the periphery triggers the early phase of the febrile response to infection and may contribute to later phases. It can be hypothesized that peripherally synthesized PGE2 transmits febrigenic signals to the brain via vagal afferent nerves. Before testing this hypothesis, we investigated whether the febrigenic effect of intravenously administered PGE2 is mediated by the brain and is not the result of a direct action of PGE2 on thermoeffectors. In anesthetized rats, intravenously injected PGE2 (100 microg/kg) caused an increase in sympathetic discharge to interscapular brown adipose tissue (iBAT), as well as increases in iBAT thermogenesis, end-expired CO2, and colonic temperature (Tc). All these effects were prevented by inhibition of neuronal function in the raphe region of the medulla oblongata using an intra-raphe microinjection of muscimol. We then asked whether the brain-mediated PGE2 fever requires vagal signaling and answered this question by conducting two independent studies in rats. In a study in anesthetized rats, acute bilateral cervical vagotomy did not affect the effects of intravenously injected PGE2 (100 microg/kg) on iBAT sympathetic discharge and Tc. In a study in conscious rats, administration of PGE2 (280 microg/kg) via an indwelling jugular catheter caused tail skin vasoconstriction, tended to increase oxygen consumption, and increased Tc; none of these responses was affected by total truncal subdiaphragmatic vagotomy performed 2 wk before the experiment. We conclude that the febrile response to circulating PGE2 is mediated by the brain, but that it does not require vagal afferent signaling.

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Prostaglandin E2 enhances the sensitizing effect of hyperthermia on pulmonary C-fibers in rats

Cited by 7 publications

References 30 publications

Why does ticagrelor induce dyspnea?

Why does ticagrelor induce dyspnea?

Vagal afferent nerves with the properties of nociceptors

Fever response to intravenous prostaglandin E₂ is mediated by the brain but does not require afferent vagal signaling

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Prostaglandin E2 enhances the sensitizing effect of hyperthermia on pulmonary C-fibers in rats

Cited by 7 publications

References 30 publications

Why does ticagrelor induce dyspnea?

Why does ticagrelor induce dyspnea?

Vagal afferent nerves with the properties of nociceptors

Fever response to intravenous prostaglandin E2 is mediated by the brain but does not require afferent vagal signaling

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Fever response to intravenous prostaglandin E₂ is mediated by the brain but does not require afferent vagal signaling