Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK 1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK 1 receptor agonist is sensitive to brain penetrating antagonists of either NK 1 , NK 2 , or NK 3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet -SP) NK 1 receptor agonist, an NK 2 receptor agonist (GR64349), or an NK 3 receptor agonist (Pro 7 -NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK 1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK 1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK 1 -, but not NK 2 -or NK 3 -receptor antagonists. Neither the selective, non-penetrating NK 1 receptor agonists, nor the selective NK 2 -or NK 3 -receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK 1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK 1 -ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK 1 receptors in SP-induced vomiting, and a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. facilitatory role for gastrointestinal NK 1 receptors. In addition, the...

No abstract

No abstract

This version is distributed under a non-commercial no derivatives Creative Commons (CC-BY-NC-ND) user license, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and not used for commercial purposes. Further, the restriction applies that if you remix, transform, or build upon the material, you may not distribute the modified material.

Ungulates have become abundant in many temperate forests, shifting tree species composition by browsing and altering soil physical conditions by trampling. Whether these effects cascade down to

No abstract

Xenobiotic cannabinoid CB 1 /CB 2 -receptor agonists appear to possess broad-spectrum antiemetic activity since they prevent vomiting produced by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, serotonin 5-HT 3 -receptor agonists, dopamine D 2 /D 3 -receptor agonists and morphine, via the stimulation of CB 1 -receptors. The purpose of this study was to evaluate whether structurally diverse cannabinoids [Δ 9 -THC, (delta -9-tetrahydrocannabinol); (Δ 8 -, can prevent radiation-induced emesis. Exposure to total body radiation (0, 5, 7.5 and 10 Gy) caused robust emesis in the least shrew (Cryptotis parva) in a dose-dependent manner (ED 50 = 5.99 (5.77 -6.23) Gy) and all animals vomited at the highest tested dose of radiation. In addition, the radiation exposure reduced locomotor behaviors to a significant but mild degree in a non-dose-dependent fashion up to one hour posttreatment. Radiation-induced emesis (10 Gy) was blocked in a dose-dependent manner by the CB 1 /CB 2 -receptor agonists with the following ID 50 potency order: CP55,940 (0.11 (0.09 -0.12) mg/kg) > WIN55, 212,2 (3.65 (3.15 -4.23) mg/ kg) = Δ 8 -THC (4.36 (3.05 -6.22) mg/kg) > Δ 9 -THC (6.76 (5.22 -8.75) mg/kg). Although the greater antiemetic potency and efficacy of Δ 8 -THC relative to its isomer Δ 9 -THC is unusual as the latter cannabinoid possesses higher affinity and potency for cannabinoid receptors in functional assays, the current data support the results of a clinical study in children suggestive of complete protection from emesis by Δ 8 -THC. This effect has not been clinically observed for Δ 9 -THC in cancer patients receiving chemo-or radiation-therapy.Cannabinoids prevented the induced emesis via the stimulation of cannabinoid CB 1 -receptors because the CB 1 (SR141716A) -and not the CB 2 (SR144528) -receptor antagonist reversed both the observed reduction in emesis frequency and shrew emesis protection afforded by either Δ 9 -THC or CP55,940 against radiation-induced emesis. These findings further suggest that the least shrew can be utilized as a versatile and inexpensive small animal model to rapidly screen the efficacy of investigational antiemetics for the prevention of radiation-induced emesis.

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl-)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to membranes (K i ϭ 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC 50 ϭ 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT 2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT 2A receptor versus 5-HT 2C and 5-HT 2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC 50 ϭ 8.7 and 23.1 nM, respectively).Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC 50 ϭ 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT 2A receptor antagonist with potent activity on platelets and vascular smooth muscle.Serotonin (5-hydroxytryptamine, 5-HT) is a naturally occurring indoleamine found primarily in brain, enterochromaffin tissue, and platelets. 5-HT exerts a multitude of biological effects mediated through interaction with specific cell surface G-protein-coupled receptors (GPCRs). To date, at least 14 different human 5-HT GPCRs are known (Kaumann and Levy, 2006). Among them, 5-HT 2A receptors on vascular smooth muscle cells and platelets play an important role in the regulation of cardiovascular function.The uptake process and storage capacity for 5-HT by platelets are such that minimal amounts of the amine exist in normal plasma. However, upon platelet activation at sites of vessel injury, 5-HT is released from the dense granules in platelets (Ashton et al., 1986). Although 5-HT by itself is only a weak activator of platelet aggregation, it effectively amplifies aggregation induced by other agonists including collagen, ADP, epinephrine, and thrombin (De Clerck and Herman, 1983;De Clerck and Janssen, 1990). Thus, 5-HT This work was supported by Arena Pharmaceuticals, Inc. Article, publication date, and citation information can be found at