Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion.

Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat.

Bradykinin-induced mechanical hyperalgesia is sympathetically dependent and B(2)-type bradykinin receptor-mediated in the rat; however, a sympathetically independent component of bradykinin hyperalgesia is shown after subdiaphragmatic vagotomy. We evaluated the mechanism of this bradykinin-induced sympathetic-independent mechanical hyperalgesia. The dose-response curve for bradykinin mechanical hyperalgesia in sympathectomized plus vagotomized rats was similar in magnitude to that for sympathetically dependent bradykinin hyperalgesia in normal rats.

Vagal modulation of bradykinin-induced mechanical hyperalgesia in the female rat.

In male rats, activity in subdiaphragmatic vagal afferents modulates nociception via an adrenal medulla-dependent mechanism. Because both the vagus and adrenal medullae are sexually dimorphic, we evaluated vagotomy-induced changes in mechanical nociceptive threshold and inflammatory hyperalgesia in female rats and compared them to those previously reported in male rats. We have found that (1) mechanical nociceptive threshold is lower in female rats than in male rats, perhaps because of tonic release of adrenal medullary factors in female rats; (2) mechanical nociceptive threshold in female rats is influenced to a lesser degree by activity in the subdiaphragmatic vagus; (3) vagotomy-induced enhancement of bradykinin hyperalgesia is greater in female rats; (4) in female rats, in contrast to male rats, celiac plus celiac accessory branch vagotomy failed to fully account for the enhancement of bradykinin hyperalgesia in complete subdiaphragmatic vagotomy; and (5) in female rats, in contrast to male rats, adrenal medullectomy plus subdiaphragmatic vagotomy only partially (approximately 30%) reversed the effect of vagotomy on bradykinin hyperalgesia.

Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat.

Vagal afferent activity modulates mechanical nociceptive threshold and inflammatory mediator-induced hyperalgesia, effects that are mediated by the adrenal medulla. To evaluate the role of epinephrine, the major hormone released from the adrenal medulla, the beta2-adrenergic receptor antagonist ICI 118,551 was chronically administered to vagotomized rats and epinephrine to normal rats. In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated vagotomy-induced enhancement of bradykinin hyperalgesia but had no effect on nociceptive threshold.