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Selected AbstractsLow-threshold heat response antagonized by capsazepine in chick sensory neurons, which are capsaicin-insensitiveEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2000Antonia Marín-Burgin Abstract The heat-transducing receptor VR1 cloned from rat sensory neurons can be activated by both noxious heat and capsaicin. As the response of sensory neurons to capsaicin is species dependent, it is conceivable that the responses to noxious heat and to capsaicin are transduced by distinct receptors across different species. Therefore, we investigated responses to noxious heat from a capsaicin-insensitive (chick) and a capsaicin-sensitive (rat) species. In chick, whole-cell patch-clamp experiments in isolated dorsal root ganglion neurons revealed two populations of neurons with different thresholds to noxious heat, activated at ,,43 °C and ,,53 °C. In cobalt uptake experiments, the proportion of neurons showing a heat-induced response increased with increasing heat stimuli. Application of capsaicin (1,10 ,m) did not result in inward currents or cobalt uptake. Rat neurons yielded comparable results in heat experiments, but were capsaicin-sensitive. Although chick neurons are insensitive to capsaicin, the competitive capsaicin antagonist capsazepine (1,10 ,m) was effective in blocking heat-induced responses, verified by patch-clamp and cobalt uptake methods. The noncompetitive capsaicin antagonist ruthenium red (10 ,m) reduced to almost nil the proportion of heat-responsive neurons identified with the cobalt uptake method. These findings suggest that chick DRG neurons express a low-threshold heat-transducing receptor with a pharmacological profile distinct from the low-threshold heat receptor VR1 cloned from rat DRG neurons. The data support the idea that there might be heat receptor subtypes with differences in the capsaicin binding site. [source] Characterization of a novel G-protein coupled receptor from the parasitic nematode H. contortus with high affinity for serotoninJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Martin W. Smith The neurotransmitter serotonin (5HT) has been shown to modulate mobility, feeding, egg-laying, and defecation behaviors in the saprophytic nematode Caenorhabditis elegans. Although the effects of serotonin on these behaviors in parasitic nematodes is under study, little is known about the diversity, ontogeny, signaling, and pharmacology of serotonin receptors in these organisms. In an effort to increase our understanding of this system, we cloned and characterized a novel cDNA (5HT1Hc) from the parasitic nematode Haemonchus contortus that has high amino acid sequence homology with known G-protein coupled 5HT1-receptors from invertebrates and vertebrates. Transcript expression studies in four development stages (egg, L1/L2, L3, and adult) revealed the presence of the mRNA in the L1/L2, L3, and adult stages. Membranes from insect cells (Sf9) expressing the 5HT1Hc -receptor cDNA displayed nanomolar binding affinity to serotonin and a unique pharmacological profile distinct from known invertebrate and mammalian 5HT-receptors. Receptor signaling studies with mammalian AV12 cells expressing the 5HT1Hc -receptor and the promiscuous G-protein, G,15, demonstrated dose-dependent intracellular signals with serotonin acting as an agonist. Together, these studies describe a novel invertebrate 5HT-receptor with high affinity for the indolealkylamine, serotonin, and pharmacological properties that do not conform to any known members of this superfamily of metabotropic receptors. [source] Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma,THE JOURNAL OF PATHOLOGY, Issue 5 2009Daniel Royston Abstract The invasion of lymphatic vessels by colorectal cancer (CRC) and its subsequent spread to draining lymph nodes is a key determinant of prognosis in this common and frequently fatal malignancy. Although tumoural lymphangiogenesis is assumed to contribute to this process, review of the current literature fails to support any notion of a simple correlation between lymphatic vessel density and CRC metastasis. Furthermore, attempts to correlate the expression of various lymphangiogenic growth factors, most notably VEGF-C and VEGF-D, with the lymphatic metastasis of CRC have provided contradictory results. Recent evidence from animal and human models of tumour metastasis suggests that complex functional and biochemical interactions between the microvasculature of tumours and other cell types within the tumour microenvironment may play a pivotal role in the behaviour of commonly metastasizing tumours. Indeed, previous insights into tumoural blood vessels have provided candidate markers of tumoural angiogenesis that are currently the subject of intense investigation as future therapeutic targets. In this review article we survey the current evidence relating lymphangiogenesis and lymphangiogenic growth factor production to metastasis by CRC, and attempt to provide some insight into the apparent discrepancies within the literature. In particular, we also discuss some new and provocative insights into the properties of tumoural lymphatics suggesting that they have specific expression profiles distinct from those of normal lymphatic vessels and that appear to promote metastasis. These findings raise the exciting prospect of future biomarkers of lymphatic metastasis and identify potential targets for new generation anti-tumour therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Investigation of the potential pharmacokinetic and pharmaco-dynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing in rats using intracerebral microdialysisBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2006Sangeeta Raje Abstract Purpose. AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. Methods. Male Sprague Dawley rats (,300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. Results. No significant (p<0.05) differences were found in the PK parameters of AHN 1-055 alone (Vdss=18.7 l/kg, Cl=1.8 l/h/kg and t1/2=7.69 h) or AHN 1-055 with cocaine (Vdss=17.4 l/kg, Cl=1.9 l/h/kg and t1/2=6.82 h). The brain-to-plasma (B/P) ratios (B/PAHN 1,055=4.8 vs B/Pwith cocaine=4.4) and half-lives (t1/2(AHN 1,055)=6.2 h vs t1/2(cocaine)=5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after co-administration with cocaine. There were no differences in the IC50 for AHN 1-055, with cocaine, however, the IC50 for cocaine was significantly reduced with AHN 1-055. Conclusions. The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse. Copyright © 2006 John Wiley & Sons, Ltd. [source] | |||||||||||||