The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT₁ and CysLT₂. The CysLT₁ receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT₂ receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT₁-receptor-mediated effects, and the role of the CysLT₂ receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT₂-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.

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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...

Cisplatin chemotherapy frequently causes severe vomiting in two temporally-separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB 1 , CB 2 ), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10 mg/kg ip), and one of vehicle, Δ 9 -THC, or both Δ 9 -THC and the CB 1 receptor antagonist SR141716A (2 mg/kg ip), and monitored for vomiting. Δ 9 -THCpretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fosimmunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB 1 receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB 2 receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin-and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Δ 9 -THC mediated by CB 1 receptors.

Communication between neurons in the mammalian brain is primarily through chemical synapses; however, evidence is accumulating in support of electrical synaptic transmission between some neuronal types in the mature nervous system. The authors have recently demonstrated that the gap junction (GJ) blocker quinidine suppresses stimulus-induced and dopamine-evoked coupling of gamma amino butyric acid (GABA) neurons in the ventral tegmental area (VTA) of mature rats (Stobbs et al., 2004). The aim of this study was to evaluate the role of connexin-36 (Cx36) GJs in mediating electrical coupling between VTA GABA neurons in P50-80 rats in vivo and P25-50 rats in vitro. Single stimulation of the internal capsule (IC) evoked VTA GABA neuron spike couplets in mature rats when activated antidromically, and multiple poststimulus spike discharges (PSDs) when activated with brief high-frequency stimulation of the IC (ICPSDs). The Cx36 GJ blocker mefloquine (30 mg/kg) suppressed VTA GABA neuron ICPSDs in mature freely behaving rats. VTA GABA neurons recorded via whole-cell patch clamp in the midbrain slice preparation of P25-50 rats showed robust expression of Cx36 transcripts when tested with single-cell quantitative reverse transcription polymerase chain reaction. In P50-80 rats, Cx36 protein immunoreactivity was evident in the VTA and surrounding structures. Dye-coupling between VTA neurons was observed following Neurobiotin labeling of VTA GABA neurons, as well as with the fluorochrome Alexa Fluor 488 using real-time video fluorescent microscopy. Thus, mature VTA GABA neurons appear to be connected by electrical synapses via Cx36 GJs, whose coupling is enhanced by corticotegmental input and by dopamine.