Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro

Abstract

The two recently isolated hypothalamic peptides orexin A and orexin B, also known as hypocretin 1 and 2, are reported to be important signaling molecules in feeding and sleep/wakefulness. Orexin-containing neurons in the lateral hypothalamus project to numerous areas of the rat brain and spinal cord including the intermediolateral cell column (IML) of the thoracolumbar spinal cord. An in vivo and in vitro study was undertaken to evaluate the hypothesis that orexins, acting on sympathetic preganglionic neurons (SPNs) in the rat spinal cord, increase sympathetic outflow. First, orexin A (0.3, 1, and 10 nmol) by intrathecal injection increased mean arterial pressure (MAP) and heart rate (HR) by an average of 5, 18, and 30 mmHg and 10, 42, and 85 beats/min in urethane-anesthetized rats. Intrathecal injection of saline had no significant effects. Orexin B (3 nmol) by intrathecal administration increased MAP and HR by an average of 11 mmHg and 40 beats/min. The pressor effects of orexin A were attenuated by prior intrathecal injection of orexin A antibodies (1:500 dilution) but not by normal serum albumin. Intravenous administration of the alpha(1)-adrenergic receptor antagonist prazosin (0.5 mg/kg) or the beta-adrenergic receptor antagonist propranolol (0.5 mg/kg) markedly diminished, respectively, the orexin A-induced increase of MAP and HR. Second, whole cell patch recordings were made from antidromically identified SPNs of spinal cord slices from 12- to 16-day-old rats. Superfusion of orexin A or orexin B (100 or 300 nM) excited 12 of 17 SPNs, as evidenced by a membrane depolarization and/or increase of neuronal discharges. Orexin A- or B-induced depolarizations persisted in TTX (0.5 microM)-containing Krebs solution, indicating that the peptide acted directly on SPNs. Results from our in vivo and in vitro studies together with the previous observation of the presence of orexin A-immunoreactive fibers in the IML suggest that orexins, when released within the IML, augment sympathetic outflow by acting directly on SPNs.

Intrathecal bombesin is sympathoexcitatory and pressor in rat

“…Compared with the effects of other peptides in identical experimental preparations, intrathecal orexin A, neuromedin U, and PACAP all cause sympathoexcitation but have distinct blood pressure effects: orexin A causes a rise in blood pressure, neuromedin U has a biphasic effect, while PACAP has no effect on blood pressure (2,17,63). Bombesin, by contrast, increased blood pressure and sSNA.…”

Antiallodynic Effects of Intrathecal Orexins in a Rat Model of Postoperative Pain

“…It seems that there is little potential for orexins alone to be served clinically as an intrathecal treatment of postoperative pain. Besides, the exophthalmos and cardiovascular excitation (Chen et al, 2000;Antunes et al, 2001) induced by central administration of orexins might deter its clinical potential. However, it still remains to be elucidated if other related orexin receptor agonists, when available, can be used as adjuvant analgesics in the treatment of postoperative pain.…”

Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B

“…Conversely, it has been shown that although genetic ablation of orexin neurons in mice causes hypophagia (Hara et al 2001), these mice develop late-onset obesity indicating a possible further role of orexins in energy expenditure. Indeed, orexins have been shown to be involved in modulating metabolic rate via stimulation of the sympathetic nervous system (Antunes et al 2001), and regulation of energy expenditure and thermogenesis (Szekely et al 2002, Yasuda et al 2005. Interestingly, in obese as compared with non-obese humans, orexin-A levels have been reported to be significantly lower (Adam et al 2002), suggesting that orexin-A is involved in the regulation of human energy metabolism at the peripheral level or non-centrally.…”