Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

Abstract

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...

Evidence for a Re-Evaluation of the Neurochemical and Anatomical Bases of Chemotherapy-Induced Vomiting

“…Indeed, Fos-immunoreactivity is frequently noted in the ENS independent of emesis. 92 However, in vomiting least shrews, a modest but significant increase in Fos-immunoreactivity in the ENS was found. In addition, selective ablation of NK 1 receptors at a limited region of the least shrew small intestine by the targeted toxin SSP-saporin significantly attenuated the vomiting frequency and altered the quality of emesis produced by the NK 1 agonist GR73632.…”

“…Indeed, recent evidence in the least shrew demonstrates that intraperitoneal administration not only of SP but also of brain-penetrable selective NK 1 agonists such as GR73632 induces vomiting in a dose-sensitive and NK 1 antagonist-sensitive manner. 92 Moreover, selective agonists of NK 2 and NK 3 receptors lacked emetogenicity, and their selective antagonists failed to prevent GR73632-induced vomiting in this species. To decipher the contribution of central/peripheral components of NK 1 receptor activation in the induced emesis, the antiemetic potential of several classes of NK 1 receptor blockers (e.g., CP99,994; CP122,721; GR203,040; GR205,171;…”

Expression and distribution of SP and its NK1 receptor in the brain-gut axis in neonatal maternally separated rat model with visceral hypersensitivity

“…SP, a neuropeptide, contains 11 amino acids, belongs to tachykinin family of peptides, and is an excitatory neurotransmitter in the bowel (Lecci et al, 2006). It has been identified in the mammalian nerve tissues, including the brain, spinal cord, and the enteric nervous system of the gut (Lecci et al, 2006;Darmani et al, 2008). SP stimulates nerves and triggers a nociceptive pain sensation via sensory nerves to enhance the motility of the gut.…”

Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—state of the art

“…Preclinical models, such as the ferret [1] and the least shrew [2], with emetic responses similar to those in patients, can be used to identify agents that may have antiemetic properties against standard challenge agents and can also be used to characterize the potency and time course of antiemetic activity, placing these agents in perspective to those currently in clinical use. Phase I trials in normal subjects may be employed to characterize toxicity and pharmacokinetic parameters as well as exploring potential drug interactions.…”