Synergistic antiemetic interactions between serotonergic 5-HT 3 and tachykininergic NK 1 -receptor antagonists in the least shrew (Cryptotis parva) Nissar A. Darmani ⁎, Seetha Chebolu, Barry Amos, Tursun Alkam Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA abstract article info Article history: Received 29 March 2011 Received in revised form 16 May 2011 Accepted 22 May 2011 Available online 13 June 2011 Keywords: 5-HT 3 receptor NK 1 receptor 2-methyl 5-HT GR73632 Synergistic Emesis Least shrew Cross-talk Interaction Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT 3 - and tachykininergic NK 1 -receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT 3 - and NK 1 -receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT 3 (tropisetron)- or an NK 1 (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4–20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8–12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose–response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT 3 - and NK 1 -receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each specific emetogen. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Serotonin (5-hydroxytryptamine = 5-HT) is a monoamine neurotransmitter present in both the central and peripheral nervous systems (Darmani and Ray, 2009). 5-HT produces its diverse effects via stimulation of seven different classes of serotonergic receptors (5-HT 1 –5-HT 7 ) many of which possess multiple subtypes. In regard to vomiting, both serotonin 5-HT 3 (an ion-gated channel) and 5-HT 4 (a G protein-coupled receptor) receptor agonists have emetic efficacy, while 5-HT 3 receptor antagonists are the main defense against the acute phase of chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving chemotherapy (Andrews and Rudd, 2004; Darmani and Ray, 2009; Feyer and Jordan, 2011). The established dogma regarding emetic neurotransmitters involved in CINV suggests that chemotherapeutics agents such as cisplatin induce their acute vomiting phase by releasing 5-HT from enterochromaffin cells in the gastro-intestinal tract (GIT) to stimulate local 5-HT 3 receptors found on the GIT vagal afferents, which subsequently activate the brainstem dorsal vagal complex (DVC) emetic nuclei [area postrema (AP), nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMNX)] to complete the vomiting reflex (Rudd and Andrews, 2005). The delayed CINV phase has been assumed to be due to activation of brainstem tachykininergic NK 1 receptors subsequent to the release of SP in the DVC (Andrews and Rudd, 2004). The mammalian tachykinins include the peptides substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) (Darmani and Ray, 2009). These peptides activate three tachykininergic receptors (NK 1 , NK 2 and NK 3 ) in both the CNS and periphery. The latter receptors belong to the family of G protein-coupled receptors that are respectively recognized with moderate selectivity by endogenous SP, NKA and NKB. While NK 1 receptor-selective agonists induce vomiting (Darmani et al., 2008), selective NK 1 antagonists not only prevent vomiting caused by NK 1 receptor agonists (Darmani et al., 2008), but also act as broad- spectrum antiemetics against a diverse array of centrally- and peripherally-acting emetogens in several animal models of emesis Pharmacology, Biochemistry and Behavior 99 (2011) 573–579 ⁎ Corresponding author. Tel.: + 1 909 469 5654; fax: +1 909 469 5698. E-mail address: ndarmani@westernu.edu (N.A. Darmani). 0091-3057/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2011.05.025 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh