Ultra-low doses of methamphetamine suppress 5-hydroxytryptophan-induced head-twitch response in mice during aging.

The head-twitch response (HTR) in mice is considered a behavioral assay for activation of 5-HT 2A receptors in rodents. It can be evoked by direct-acting 5-HT 2A receptor agonists such as (±)-2,5-dimethoxy-4-iodoamphetamine, 5-hydroxytryptamine precursors [e.g.

A Comparative Study of the Antiemetic Effects of α-Adrenergic Receptor Agonists Clonidine and Dexmedetomidine against Diverse Emetogens in the Least Shrew () Model of Emesis.

In contrast to cats and dogs, here we report that the α-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.

RNA sequencing least shrew () brainstem and gut transcripts following administration of a selective substance P neurokinin NK receptor agonist and antagonist expands genomics resources for emesis research.

The least shrew is among the subset of animals that are capable of vomiting and therefore serves as a valuable research model for investigating the biochemistry, molecular biology, pharmacology, and genomics of emesis. Both nausea and vomiting are associated with a variety of illnesses (bacterial/viral infections, bulimia, exposure to toxins, gall bladder disease), conditions (pregnancy, motion sickness, emotional stress, overeating) and reactions to drugs (chemotherapeutics, opiates). The severe discomfort and intense fear associated with the stressful symptoms of nausea and emesis are the major reason for patient non-compliance when being treated with cancer chemotherapeutics.

Effects of low-doses of methamphetamine on d-fenfluramine-induced head-twitch response (HTR) in mice during ageing and c-fos expression in the prefrontal cortex.

Background: The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT receptor agonists such as ( ±)- 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC.

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew ().

Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.

Providing an environmental management model with emphasis on ecosystem resilience: a coastal City in Southern Iran.

Urban environmental management is an effective tool which aims at urban development inline with environmental, social and economic values. The present study aims to provide an environmental management model of Bandar Abbas with an emphasis on ecosystem resilience. The research has been conducted in several steps, the first of which includes the assessment and analysis of resilience of Bandar Abbas city in terms of environmental dimensions and components based on the selection of environmental indicators and components in accordance with the opinions of urban issues experts and access to the available data and information resources, estimation and evaluation of the resilience status of indicators and components of the city.

An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT-receptor mediated head-twitch response in mice.

Background: Methamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.

Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).

Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the least shrew (Cryptotis parva).

The Contribution of Phospholipase C in Vomiting in the Least Shrew (Cryptotis Parva) Model of Emesis.

Gq and Gβγ protein-dependent phospholipase C (PLC) activation is extensively involved in G protein-coupled receptor (GPCR)-mediated signaling pathways which are implicated in a wide range of physiological and pathological events. Stimulation of several GPCRs, such as substance P neurokinin 1-, dopamine D-, histamine H- and mu-opioid receptors, can lead to vomiting. The aim of this study was to investigate the role of PLC in vomiting through assessment of the emetic potential of a PLC activator (m-3M3FBS), and the antiemetic efficacy of a PLC inhibitor (U73122), in the least shrew model of vomiting.

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems.

Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g.

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew ().

Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects.

Signal transduction pathways involved in dopamine D receptor-evoked emesis in the least shrew (Cryptotis parva).

With its five receptor subtypes (D), dopamine is implicated in a myriad of neurological illnesses. Dopamine D receptor-based agonist therapy evokes nausea and vomiting. The signaling mechanisms by which dopamine D receptors evoke vomiting remains unknown.

Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern.

Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function.

Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects.

The pivotal role of glycogen synthase kinase 3 (GSK-3) in vomiting evoked by specific emetogens in the least shrew (Cryptotis parva).

Glycogen synthase kinase 3 (GSK-3) is a constitutively active multifunctional serine-threonine kinase which is involved in diverse physiological processes. GSK-3 has been implicated in a wide range of diseases including neurodegeneration, inflammation, diabetes and cancer. GSK-3 is a downstream target for protein kinase B (Akt) which phosphorylates GSK-3 and suppresses its activity.

Δ-THC and related cannabinoids suppress substance P- induced neurokinin NK-receptor-mediated vomiting via activation of cannabinoid CB receptor.

Δ-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT-and neurokinin NK-receptors to induce vomiting. Δ-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT receptor selective agonist, 2-methyserotonin.

Ultra-low doses of the transient receptor potential vanilloid 1 agonist, resiniferatoxin, prevents vomiting evoked by diverse emetogens in the least shrew (Cryptotis parva).

Published studies have shown that the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, resiniferatoxin (RTX), has pro and antiemetic effects. RTX can suppress vomiting evoked by a variety of nonselective emetogens such as copper sulfate and cisplatin in several vomit-competent species. In the least shrew, we have already demonstrated that combinations of ultra-low doses of RTX and low doses of the cannabinoid CB1/2 receptor agonist delta-9-tetrahydrocannabinol (Δ-THC) produce additive antiemetic effects against cisplatin-evoked vomiting.

Intracellular emetic signaling cascades by which the selective neurokinin type 1 receptor (NKR) agonist GR73632 evokes vomiting in the least shrew (Cryptotis parva).

To characterize mechanisms involved in neurokinin type 1 receptor (NKR)-mediated emesis, we investigated the brainstem emetic signaling pathways following treating least shrews with the selective NKR agonist GR73632. In addition to episodes of vomiting over a 30-min observation period, a significant increase in substance P-immunoreactivity in the emetic brainstem dorsal motor nucleus of the vagus (DMNX) occurred at 15 min post an intraperitoneal (i.p.

Intracellular emetic signaling evoked by the L-type Ca channel agonist FPL64176 in the least shrew (Cryptotis parva).

Ca plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus.

The anti-asthmatic drug pranlukast suppresses the delayed-phase vomiting and reverses intracellular indices of emesis evoked by cisplatin in the least shrew (Cryptotis parva).

The introduction of second generation serotonin 5-HT receptor (5-HT) antagonist palonosetron combined with long-acting substance P neurokinin NK receptor (NK) antagonists (e.g. netupitant) has substantially improved antiemetic therapy against early- and delayed-phases of emesis caused by highly emetogenic chemotherapeutics such as cisplatin.

Histological Characteristics of the Tracheobronchial Tree of the Least Shrew (Cryptotis Parva).

The least shrew (Cryptotis parva) is a small vomit-competent insectivorous species which has recently been introduced as an emesis animal model in the laboratory. In this study, the respiratory system of the least shrew was examined and compared with the well-established larger species routinely used in the laboratory. Five least shrews (4-5 g body weight, 45-60 days old) were used.

Intracellular vomit signals and cascades downstream of emetic receptors: Evidence from the least shrew () model of vomiting.

Nausea and vomiting are often considered as stressful symptoms of many diseases and drugs. In fact they are the most feared and debilitating side-effects of many cancer chemotherapeutics and the main cause of patient noncompliance. Despite years of substantial research, the intracellular emetic signals are at best poorly understood or remain unknown.

Ca signaling and emesis: Recent progress and new perspectives.

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK, serotonergic 5-HT, dopaminergic D, cholinergic M, or histaminergic H) whose activation in vomit-competent species can evoke emesis.