Effects of a selective neuropeptide Y Y₂ receptor antagonist, BIIE0246, on Y₂ receptors at peripheral neuroeffector junctions

Abstract

1 This study investigated the eects of BIIE0246, a novel neuropeptide Y (NPY) Y 2 receptor antagonist, on the inhibition of cholinergic neuroeector transmission in rat heart and guinea-pig trachea and purinergic neuroeector transmission in guinea-pig vas deferens produced by the NPY Y 2 receptor agonist, N-acetyl [Leu 28,31 ] NPY 24-36. 2 In pentobarbitone anaesthetized rats, supramaximal stimulation every 30 s, of the vagus nerve innervating the heart, increased pulse interval by approximately 100 ms. This response was attenuated by intravenous administration of N-acetyl [Leu 28,31 ] NPY 24-36 (10 nmol kg ] NPY 24-36 but had no eect when applied alone. 6 The ®ndings support the view that the nerve terminals of postganglionic parasympathetic and sympathetic neurones possess neuropeptide Y Y 2 receptors which, when activated, reduce neurotransmitter release.

Neuropeptide Y Gates a Stress-Induced, Long-Lasting Plasticity in the Sympathetic Nervous System

“…In these experiments, we used an in vivo paradigm, the cold-water forced swim test (FST). This mixed stressor (Kvetnansky et al, 2009) induces synaptic plasticity in the CNS (Saal et al, 2003;Campioni et al, 2009). Using this approach, we find that a local peptidergic signaling pathway tonically suppresses adrenal catecholamine release but that acute stress overrides this negative feedback loop and leads to an increase in adrenal secretory capacity that lasts far longer than the initiating stimulus.…”

“…Mice (usually P21-P23) were individually housed for 3-5 d and then either exposed to the cold-water FST or left undisturbed. Experimental animals were placed in cold (4 -5°C) water for 5-6 min (cold-water FST) as described previously (Saal et al, 2003;Campioni et al, 2009). After recovery under an infrared heat lamp for 15-25 min, the animals were returned to their home cage.…”

“…For example, severe hypoglycemia leads to increased release of epinephrine and cortisol (Watts and Donovan, 2010), and circulating levels of both hormones subsequently decline (Widmaier, 1989;Ritter et al, 2006). However, a transient stress can have lasting consequences.…”

“…Exposure to stress triggers a coordinated response involving two adrenal-dependent pathways: (1) the hypothalamic-pituitaryadrenal (HPA) axis and (2) the sympathetic-adrenal system (Sapolsky et al, 2000;. HPA activation evokes cortisol secretion from the adrenal cortex, whereas increased activity in the sympathetic-adrenal system provokes elevated catecholamine release (primarily epinephrine) from chromaffin cells in the adrenal medulla.…”

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

“…YRs together with their three native ligands, NPY, pancreatic polypeptide (PP), and peptide YY (PYY), form a multiligand/ multireceptor system (8), which is involved in many important physiological processes, such as regulation of food intake (9), control of blood pressure, and regulation of pancreatic and gastric secretion (10). The Y 2 R is predominantly expressed as a 381-amino acid protein in the brain cortex (11,12), hippocampus, intestine, and certain blood vessels (8,13,14) and is involved in the inhibition of neurotransmitter release (15), regulation of memory retention (16), circadian rhythm, and angiogenesis (13), which makes it an attractive target for drug development. Potent Y 2 R agonists were suggested as therapy for epilepsy, because Y 2 R selective ligands have been shown to reduce epileptic seizures (17).…”