Istvan Nagy

Publications of Istvan Nagy

• Xenon fails to inhibit capsaicin-evoked CGRP release by nociceptors in culture.

  Authors: Guy Calcott, John P M White, Istvan Nagy

  Neuroscience letters. 07/2011; 499(2):124-6.

  To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing,To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing, we examined the effect of xenon in reducing the release of calcitonin gene-related peptide (CGRP) from those neurons. We found that exposure to xenon failed to effect a reduction of capsaicin-evoked CGRP release from cultured primary sensory neurons when stimulated by capsaicin. This finding suggests that xenon acts on several molecular targets on nociceptive primary sensory neurons, and that xenon's action on one, or more, of those targets serves to offset the inhibitory, pro-analgesic, effect of xenon on TRPV1. It is concluded that xenon may not produce any analgesic effect through peripheral nociceptors.

• Systemic inflammation enhances surgery-induced cognitive dysfunction in mice.

  Authors: António Rei Fidalgo, Mario Cibelli, John P M White, Istvan Nagy, Mervyn Maze, Daqing Ma

  Neuroscience letters. 07/2011; 498(1):63-6.

  The activation of the immune system, by either lipopolysaccharide (LPS) administration or surgical trauma, has been shown to be capable of affecting hippocampal function, causing memory impairment.The activation of the immune system, by either lipopolysaccharide (LPS) administration or surgical trauma, has been shown to be capable of affecting hippocampal function, causing memory impairment. Here, we examined the extent to which LPS-induced infection may aggravate impairment of memory function following orthopaedic surgery. Hippocampal memory function impairment was assessed using fear-conditioning tasks, while IL-1β levels in plasma and hippocampus were measured using ELISA. LPS-induced inflammation disrupted hippocampal memory consolidation as evidenced by reduced contextual freezing time exhibited by infected mice. Likewise, surgery caused hippocampal-dependent memory impairment, which was associated with increased levels of IL-1β both in plasma and hippocampus. However, a sub-pyrogenic dose of LPS alone failed to impair memory function. This dose of LPS, when administered prior to surgery, exacerbated surgery-induced cognitive dysfunction as evidenced by further reduction of contextual freezing time. Also, it caused a concomitant additional increase in the levels of IL-1β in both plasma and hippocampus of those animals. Our data suggest that sub-clinical infection may sensitise the immune system augmenting the severity of post-operative cognitive dysfunction.

• Severe burn injury induces a characteristic activation of extracellular signal-regulated kinase 1/2 in spinal dorsal horn neurons.

  Authors: John P M White, Chin Wing Ko, Antonio Rei Fidalgo, Mario Cibelli, Cleoper C Paule, Peter J Anderson, Celia Cruz, Szabolcs Gomba, Klara Matesz, Gabor Veress, Antonio Avelino, Istvan Nagy

  European journal of pain (London, England). 03/2011; 15(7):683-90.

  We have studied scalding-type burn injury-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptiveWe have studied scalding-type burn injury-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptive processing. At 5min after severe scalding injury to mouse hind-paw, a substantial number of phosphorylated ERK1/2 (pERK1/2) immunopositive neurons were found in the ipsilateral dorsal horn. At 1h post-injury, the number of pERK1/2-labelled neurons remained substantially the same. However, at 3h post-injury, a further increase in the number of labelled neurons was found on the ipsilateral side, while a remarkable increase in the number of labelled neurons on the contralateral side resulted in there being no significant difference between the extent of the labelling on both sides. By 6h post-injury, the number of labelled neurons was reduced on both sides without there being significant difference between the two sides. A similar pattern of severe scalding injury-induced activation of ERK1/2 in spinal dorsal horn neurons over the same time-course was found in mice which lacked the transient receptor potential type 1 receptor (TRPV1) except that the extent to which ERK1/2 was activated in the ipsilateral dorsal horn at 5 min post-injury was significantly greater in wild-type animals when compared to TRPV1 null animals. This difference in activation of ERK1/2 in spinal dorsal horn neurons was abolished within 1h after injury, demonstrating that TRPV1 is not essential for the maintenance of ongoing spinal nociceptive processing in inflammatory pain conditions in mouse resulting from at least certain types of severe burn injury.

• Molecular structure of transient receptor potential vanilloid type 1 ion channel (TRPV1).

  Authors: Laszlo Urban, John P M White, Istvan Nagy

  Current pharmaceutical biotechnology. 11/2010; 12(1):115-21.

  Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1 is comprehensively elicited. The result is that the present state of knowledge can reasonably be described as a patch-work of insightful data where major deficits in knowledge remain and where meaningful general conclusions cannot be reliably drawn. This is unfortunate, given that this ion channel has been convincingly implicated in a wide range of physiological functions and pathological conditions. Moreover, the development of therapeutic strategies which target TRPV1 depends on the knowledge of this receptor's structure and its relationship with channel function. Here, we offer a description of the present state of knowledge in relation to this complex subject.

• TRPV1 function in health and disease.

  Authors: John P M White, Laszlo Urban, Istvan Nagy

  Current pharmaceutical biotechnology. 11/2010; 12(1):130-44.

  The transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater thanThe transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater than approximately 43°C., or capsaicin, the pungent ingredient of hot chilli peppers. More importantly, however, it has been shown that TRPV1 plays a pivotal role in the development of the burning pain sensation associated with inflammation in peripheral tissues. More recently, there has been a virtual avalanche of sightings of TRPV1 on the anatomical landscape, coupled with association of TRPV1 with a wide range of non-pain-related physiological and pathological conditions. Here, we consider the continuously expanding set of functions in both health and disease which TRPV1 is understood to subserve at present. The widespread expression of TRPV1 in the human suggests that, in addition to the development of burning pain associated with acute exposure to heat or capsaicin, and with inflammation, TRPV1 may also be involved in an array of vitally important functions, such as those of the urinary tract, the respiratory and auditory systems. Moreover, TRPV1 could also be involved in the maintenance of body and cell homeostasis, metabolism, regulation of hair growth, and development of cancer. Thus, controlling TRPV1 function may possess the potential of providing exciting opportunities for therapeutic interventions. At the same time, however, the widespread distribution of these ion channels introduces a tremendous complication in developing a drug to serve in one disease context which may have profound implications for normal TRPV1 functioning in other non-pathological contexts.

• Xenon reduces activation of transient receptor potential vanilloid type 1 (TRPV1) in rat dorsal root ganglion cells and in human TRPV1-expressing HEK293 cells.

  Authors: John P M White, Guy Calcott, Agnes Jenes, Mahmuda Hossein, Cleoper C Paule, Peter Santha, John B Davis, Daqing Ma, Andrew S C Rice, Istvan Nagy

  Life sciences. 11/2010; 88(3-4):141-9.

  Xenon provides effective analgesia in several pain states at sub-anaesthetic doses. Our aim was to examine whether xenon may mediate its analgesic effect, in part, through reducing the activity ofXenon provides effective analgesia in several pain states at sub-anaesthetic doses. Our aim was to examine whether xenon may mediate its analgesic effect, in part, through reducing the activity of transient receptor potential vanilloid type 1 (TRPV1), a receptor known to be involved in certain inflammatory pain conditions. We studied the effect of xenon on capsaicin-evoked cobalt uptake in rat cultured primary sensory neurons and in human TRPV1 (hTRPV1)-expressing human embryonic kidney 293 (HEK293) cells. We also examined xenon's effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the rat spinal dorsal horn evoked by hind-paw injection of capsaicin. Xenon (75%) reduced the number of primary sensory neurons responding to the TRPV1 agonist, capsaicin (100 nM-1 μM) by ~25% to ~50%. Xenon reduced the number of heterologously-expressed hTRPV1 activated by 300 nM capsaicin by ~50%. Xenon (80%) reduced by ~40% the number of phosphorylated ERK1/2-expressing neurons in rat spinal dorsal horn resulting from hind-paw capsaicin injection. Xenon substantially reduces the activity of TRPV1 in response to noxious stimulation by the specific TRPV1 agonist, capsaicin, suggesting a possible role for xenon as an adjunct analgesic where hTRPV1 is an active contributor to the excitation of primary afferents which initiates the pain sensation.

• Extracellular signal-regulated kinases in pain of peripheral origin.

  Authors: John P M White, Mario Cibelli, Antonio Rei Fidalgo, Istvan Nagy

  European journal of pharmacology. 10/2010; 650(1):8-17.

  Activation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated withActivation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated with many inflammatory conditions, such as herniated spinal disc pain, chronic inflammatory articular pain, and the pain associated with bladder inflammation. Moreover, ERKs are implicated in the development of neuropathic pain signs in animals which are subjected to the lumbar 5 spinal nerve ligation model and the chronic constriction injury model of neuropathic pain. The position has now been reached where all scientists working on pain subjects ought to be aware of the importance of ERKs, if only because certain of these enzymes are increasingly employed as experimental markers of nociceptive processing. Here, we introduce the reader, first, to the intracellular context in which these enzymes function. Thereafter, we consider the involvement of ERKs in mediating nociceptive signalling to the brain resulting from noxious stimuli at the periphery which will be interpreted by the brain as pain of peripheral origin.

• Effects of cannabinoids on capsaicin receptor activity following exposure of primary sensory neurons to inflammatory mediators.

  Authors: Neil D Soneji, Cleoper C Paule, Marta Mlynarczyk, Istvan Nagy

  Life sciences. 07/2010; 87(5-6):162-8.

  Activation of the cannabinoid 1 (CB1) receptor in cultured primary sensory neurons reduces responses mediated through the transient receptor potential vanilloid type 1 receptor (TRPV1), which plays aActivation of the cannabinoid 1 (CB1) receptor in cultured primary sensory neurons reduces responses mediated through the transient receptor potential vanilloid type 1 receptor (TRPV1), which plays a pivotal role in the development of heat hyperalgesia and visceral hyper-reflexia in inflammatory conditions. Here, we studied the effect of cannabinoid-evoked inhibitory effect on TRPV1 in inflammatory conditions. The effect of anandamide (1 nM-30 nM) and 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (HU210; 1 microM-10 microM) was assessed on capsaicin (10 nM or 100 nM)-evoked cobalt uptake in rat cultured primary sensory neurons following the incubation of the cells in an "inflammatory environment" created by the major inflammatory mediators, bradykinin (5 microM), prostaglandin E(2) (5 microM) and nerve growth factor (100 ng/ml) for 10 min. 1 nM and 10 nM anandamide significantly reduced the 10 nM but not the 100 nM capsaicin-evoked responses. HU210 did not produce a significant change in responses evoked by capsaicin at either of its concentrations. The anandamide-induced inhibitory effect could not be reversed by the CB1 receptor antagonist, rimonabant (200 nM) or the membrane-permeable cAMP analogue, 8Br-cAMP (100 microM). These findings suggest that anandamide may inhibit TRPV1-mediated responses in a non-CB1/non-cannabinoid 2 receptor-dependent manner in primary sensory neurons in inflammatory conditions.

• The endogenous cannabinoid anandamide inhibits transient receptor potential vanilloid type 1 receptor-mediated currents in rat cultured primary sensory neurons.

  Authors: P Sántha, A Jenes, Cs Somogyi, Istvan Nagy

  Acta physiologica Hungarica. 06/2010; 97(2):149-58.

  The activity of the transient receptor potential vanilloid type 1 ion channel (TRPV1) that is expressed by the great majority of polymodal nociceptors is pivotal for the development of inflammatoryThe activity of the transient receptor potential vanilloid type 1 ion channel (TRPV1) that is expressed by the great majority of polymodal nociceptors is pivotal for the development of inflammatory heat hyperalgesia. The responsiveness of TRPV1 is regulated by a series of intracellular signalling molecules including the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA); increased or decreased PKA activity results in TRPV1 sensitisation or desensitisation, respectively. Activation of the cannabinoid 1 (CB1) receptor that is expressed by the majority of the TRPV1-expressing primary sensory neurons reduces PKA activity. Therefore, here we studied whether activation of the CB1 receptor resulted in reduced TRPV1-mediated responses in cultured rat primary sensory neurons. We found that TRPV1-mediated whole-cell currents were significantly reduced respectively, by 50% and 25% by 10 nM and 30 nM of the endogenous CB1 receptor agonist, anandamide. The PKA inhibitor, H89 (10 microM) also had a significant inhibitory effect on TRPV1-mediated currents ( approximately 70%). These findings suggest that activation of the CB1 receptor can reduce the activity of TRPV1 in primary sensory neurons, and that this inhibitory effect could be mediated through the reduction of PKA-mediated phosphorylation of TRPV1.

• Role of transient receptor potential and acid-sensing ion channels in peripheral inflammatory pain.

  Authors: John P M White, Mario Cibelli, Antonio Rei Fidalgo, Cleoper C Paule, Faruq Noormohamed, Laszlo Urban, Mervyn Maze, Istvan Nagy

  Anesthesiology. 03/2010; 112(3):729-41.

  Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of painPain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation.

• Functional Transient Receptor Potential Vanilloid 1 is Expressed in Human Urothelial Cells.

  Authors: Ana Charrua, Carlos Reguenga, João Miguel Cordeiro, Paulo Correiade-Sá, Cleope Paule, Istvan Nagy, Francisco Cruz, António Avelino

  The Journal of urology. 12/2009; 182(6):2944-50.

  PURPOSE: We investigated the expression and functional status of TRPV1 receptor in human urothelial cells. MATERIAL AND METHODS: Human urothelium was cultured and TRPV1 receptor expression wasPURPOSE: We investigated the expression and functional status of TRPV1 receptor in human urothelial cells. MATERIAL AND METHODS: Human urothelium was cultured and TRPV1 receptor expression was studied by immunocytochemistry and reverse transcriptase-polymerase chain reaction. The influence of inflammatory mediators on TRPV1 mRNA levels was also studied. Functional assays (cobalt uptake measurements and whole cell voltage clamp records) were used to study the response of urothelial cells to capsaicin, temperature, low pH and inflammatory mediators. Capsaicin induced adenosine triphosphate release from urothelial cells was assessed by bioluminescence. RESULTS: TRPV1 protein and mRNA were detected in human urothelial cells and mRNA more than tripled in the presence of inflammatory mediators. Nerve growth factor treatment alone did not affect TRPV1 mRNA expression. Capsaicin (100 nM and 1 muM) and heat (41C and 45C) evoked cobalt uptake and inflammatory mediators lowered the temperature threshold for TRPV1 activation to 37C. Capsaicin (1 muM) induced TRPV1 desensitization to further applications of the agonist. In whole cell patch clamp experiments 1 muM capsaicin and a heat ramp from 37C to 50C caused inward currents. The same concentration of capsaicin induced the release of about 7 fmol adenosine triphosphate per mg. CONCLUSIONS: TRPV1 receptors expressed by human urothelial cells respond to capsaicin and thermal stimuli. Capsaicin evoked release of adenosine triphosphate suggests that human urothelial TRPV1 is involved in the afferent branch of the micturition reflex. Inflammatory mediators decrease the TRPV1 thermal threshold of activation to body temperature and increase its expression. This finding may be relevant for symptoms associated with cystitis.

• Localization of the endocannabinoid-degrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury.

  Authors: Isobel J Lever, Michelle Robinson, Mario Cibelli, Cleoper Paule, Peter Santha, Louis Yee, Stephen P Hunt, Benjamin F Cravatt, Maurice R Elphick, Istvan Nagy, Andrew S C Rice

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 04/2009; 29(12):3766-80.

  Fatty acid amide hydrolase (FAAH) is a degradative enzyme for a group of endogenous signaling lipids that includes anandamide (AEA). AEA acts as an endocannabinoid and an endovanilloid by activatingFatty acid amide hydrolase (FAAH) is a degradative enzyme for a group of endogenous signaling lipids that includes anandamide (AEA). AEA acts as an endocannabinoid and an endovanilloid by activating cannabinoid and vanilloid type 1 transient receptor potential (TRPV1) receptors, respectively, on dorsal root ganglion (DRG) sensory neurons. Inhibition of FAAH activity increases AEA concentrations in nervous tissue and reduces sensory hypersensitivity in animal pain models. Using immunohistochemistry, Western blotting, and reverse transcription-PCR, we demonstrate the location of the FAAH in adult rat DRG, sciatic nerve, and spinal cord. In naive rats, FAAH immunoreactivity localized to the soma of 32.7 +/- 0.8% of neurons in L4 and L5 DRG. These were small-sized (mean soma area, 395.96 +/- 5.6 mum(2)) and predominantly colabeled with peripherin and isolectin B4 markers of unmyelinated C-fiber neurons; 68% colabeled with antibodies to TRPV1 (marker of nociceptive DRG neurons), and <2% colabeled with NF200 (marker of large myelinated neurons). FAAH-IR was also present in small, NF200-negative cultured rat DRG neurons. Incubation of these cultures with the FAAH inhibitor URB597 increased AEA-evoked cobalt uptake in a capsazepine-sensitive manner. After sciatic nerve axotomy, there was a rightward shift in the cell-size distribution of FAAH-immunoreactive (IR) DRG neurons ipsilateral to injury: FAAH immunoreactivity was detected in larger-sized cells that colabeled with NF200. An ipsilateral versus contralateral increase in both the size and proportion of FAAH-IR DRG occurred after spinal nerve transection injury but not after chronic inflammation of the rat hindpaw 2 d after injection of complete Freund's adjuvant. This study reveals the location of FAAH in neural tissue involved in peripheral nociceptive transmission.

• Cystitis is associated with TRPV1b-downregulation in rat dorsal root ganglia.

  Authors: Ana Charrua, Carlos Reguenga, Cleoper C Paule, Istvan Nagy, Francisco Cruz, António Avelino

  Neuroreport. 11/2008; 19(15):1469-72.

  The recently identified splice variant of the transient receptor vanilloid type 1 (TRPV1) molecule, TRPV1b, produces a negative-dominant effect on the responsiveness of the TRPV1 channel, which isThe recently identified splice variant of the transient receptor vanilloid type 1 (TRPV1) molecule, TRPV1b, produces a negative-dominant effect on the responsiveness of the TRPV1 channel, which is increased by peripheral inflammatory processes. Here, we studied, using real-time polymerase chain reaction, whether cyclophosphamide injection-evoked cystitis is associated with altered TRPV1/TRPV1b expression in the L5-L6 dorsal root ganglia, which innervate the urinary bladder. We found that while TRPV1 mRNA expression was unchanged, the amount of TRPV1b transcript was significantly reduced in L5-L6 dorsal root ganglia during cystitis. These data indicate that peripheral inflammatory events induce changes in TRPV1b expression in primary sensory neurons, which may result in increased responsiveness of the TRPV1 channel.

• Neurochemical characterization of insulin receptor-expressing primary sensory neurons in wild-type and vanilloid type 1 transient receptor potential receptor knockout mice.

  Authors: Djalil Baiou, Peter Santha, Antonio Avelino, Ana Charrua, Timea Bacskai, Klara Matesz, Francisco Cruz, Istvan Nagy

  The Journal of comparative neurology. 08/2007; 503(2):334-47.

  The insulin receptor (IR) is expressed by a subpopulation of primary sensory neurons (PSN), including a proportion of cells expressing the nociceptive transducer vanilloid type 1 transient receptorThe insulin receptor (IR) is expressed by a subpopulation of primary sensory neurons (PSN), including a proportion of cells expressing the nociceptive transducer vanilloid type 1 transient receptor potential receptor (TRPV1). Recent data suggest functional links between the IR and other receptors, including TRPV1, which could be involved in the development of PSN malfunctions in pathological insulin secretion. Here we used combined immunohistochemical labelling on sections from L4-5 dorsal root ganglia of wild-type (WT) and TRPV1 knockout (KO) mice to examine the neurochemical properties of IR-expressing PSN and the possible effect of deletion of TRPV1 on those characteristics. We found that antibodies raised against the high-molecular-weight neurofilament (NF-200) and the neurofilament protein peripherin distinguished between small and large neurons. We also found that the IR was expressed predominantly by the small peripherin-immunopositive cells both in the WT and in the KO animals. IR expression, however, did not show any preference between the major subpopulations of the small cells, the calcitonin gene-related peptide (CGRP)-expressing and Bandeiraea simplicifolia isolectin B4 (IB4)-binding neurons, either in the WT or in the KO mice. Nevertheless, a significant proportion of the IR-expressing cells also expressed TRPV1. Comparison of the staining pattern of these markers showed no difference between WT and KO animals. These findings indicate that the majority of the IR-expressing PSN are small neurons, which are considered as nociceptive cells. Furthermore, these data show that deletion of the TRPV1 gene does not induce any additional changes in neurochemical phenotype of nociceptive PSN.

• Combined Photovoltaic / Thermal Energy System for Stand-alone Operation

  Authors: Rafael K. Jardan, Istvan Nagy, Angel Cid-Pastor, Ramon Leyva, Abdelali El Aroudi, Luis Martinez-Salamero

  Industrial Electronics, 2007. ISIE 2007. IEEE International Symposium on; 07/2007

  The utilization of solar energy can be made by photovoltaic (PV) cells to generate electric power directly and solar thermal (T) panels can be applied to generate heat power. When the utilization ofThe utilization of solar energy can be made by photovoltaic (PV) cells to generate electric power directly and solar thermal (T) panels can be applied to generate heat power. When the utilization of the solar energy is necessary to generate electric power, the option of using T panels in combination with some heat / electric power conversion technology can be a viable solution. The power generated by utilizing the solar energy absorbed by a given area of solar panel can be increased if the two technologies, PV and T cells, are combined in such a way that the resulting unit will be capable of co-generation of heat and electric power. In the present paper combined Photovoltaic / Thermal panels are suggested to generate heat power to produce hot water, while the photovoltaic part is used to obtain electric power mainly for covering the electric power consumption of the system, to supply the electronic control units and to operate pump drives etc. Ac and dc supplies are provided by converters for covering self-consumption and possibly the need of some household appliances. The development and design of the system is made by extensive use of modeling and simulation techniques. In the paper a part of the simulation studies, carried out to determine the energy balance in the electric energy conversion section of the system and the control structure, assuming stand-alone operation is presented.

• Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes.

  Authors: Dorte X Gram, Bo Ahrén, Istvan Nagy, Uffe B Olsen, Christian L Brand, Frank Sundler, René Tabanera, Ove Svendsen, Richard D Carr, Peter Santha, Nils Wierup, Anker J Hansen

  The European journal of neuroscience. 02/2007; 25(1):213-23.

  The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primaryThe system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.

• Stability Analysis of PWM-Controlled Dual Channel Resonant Buck&Boost Converter Using PI Controller

  Authors: Balazs Buti, Istvan Nagy, Eisuke Masada

  Power Electronics and Motion Control Conference, 2006. EPE-PEMC 2006. 12th International; 10/2006

  The paper is concerned with the stability analysis of a feedback controlled resonant dual channel buck&boost converter. The output voltage is controlled by using constant frequency PWM and PIThe paper is concerned with the stability analysis of a feedback controlled resonant dual channel buck&boost converter. The output voltage is controlled by using constant frequency PWM and PI controller. The analysis is based on the eigenvalues of the Jacobian matrix of the Poincaré Map Function (PMF). After small perturbation determining the deviations of the state variables from the periodic trajectory, the Jacobian matrix is calculated without the need to determine the PMF itself. The introduction of the so-called auxiliary state vector greatly facilitates the calculation. Calculation and simulation results included helps the design of the control loop.

• The distribution of sensory fibers immunoreactive for the TRPV1 (capsaicin) receptor in the human prostate.

  Authors: Paulo Dinis, Ana Charrua, António Avelino, Istvan Nagy, José Quintas, Ulisses Ribau, Francisco Cruz

  European urology. 08/2005; 48(1):162-7.

  OBJECTIVES: To determine the distribution of sensory fibers immunoreactive to the pain receptor TRPV1 in the human prostate. METHODS: Eight prostates were harvested from cadaver transplant donors andOBJECTIVES: To determine the distribution of sensory fibers immunoreactive to the pain receptor TRPV1 in the human prostate. METHODS: Eight prostates were harvested from cadaver transplant donors and immediately immersion fixed. Longitudinal and transverse 20 microm sections were cut on a cryostat and immunoreacted with two anti-human TPRV1 antibodies. RESULTS: TRPV1-immunoreactive nerve fibers were distributed throughout the prostatic urethral mucosa, verumontanum, ejaculatory ducts and periurethral prostatic acini. In the urethral mucosa, TRPV1-immunoreactive fibers penetrated the epithelial layer up to its surface. In the transitional and peripheral zones of the gland no TRPV1-immunoreactive nerve fibers were detected. CONCLUSIONS: The existence of a rich TRPV1 sensory innervation in the human prostate may open new therapeutic perspectives for the treatment of pain in patients with chronic prostatitis (Chronic Pelvic Pain Syndrome).

• Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis.

  Authors: Paulo Dinis, Ana Charrua, Antonio Avelino, Mohammed Yaqoob, Stuart Bevan, Istvan Nagy, Francisco Cruz

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 01/2005; 24(50):11253-63.

  The role of anandamide in the development of inflammatory hyperalgesia and visceral hyperreflexia was studied in the rat urinary bladder. Animals were given intraperitoneal cyclophosphamideThe role of anandamide in the development of inflammatory hyperalgesia and visceral hyperreflexia was studied in the rat urinary bladder. Animals were given intraperitoneal cyclophosphamide injection, which evokes painful hemorrhagic cystitis accompanied by increased bladder reflex activity. The vanilloid receptor 1 [transient receptor potential vanilloid 1 (TRPV1)] antagonist capsazepine, applied onto the serosal surface of bladders, significantly reduced the hyperreflexia. Mass spectrometric analysis revealed that cyclophosphamide injection significantly and persistently increased the anandamide content of bladder tissues. The increase in the anandamide content paralleled the development of reflex hyperactivity. Anandamide (1-100 microm), applied onto the serosal surface of naive bladders, increased the reflex activity in a concentration-dependent manner. Repeated anandamide applications did not produce desensitization of the response. The anandamide-evoked effect was blocked by capsazepine or by instillation of resiniferatoxin, the ultrapotent TRPV1 agonist, into the bladders 24 hr before the anandamide challenge. The cannabinoid 1 receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] significantly increased the potency of anandamide in enhancing bladder reflex activity in naive but not in cyclophosphamide-injected animals. Application of the fatty acid amide hydrolyze inhibitor palmitoylisopropylamine onto the serosal surface of bladders also increased the reflex activity both in naive and cyclophosphamide-injected rats. This latter effect in naive animals was blocked by capsazepine and by resiniferatoxin pretreatment. Finally, intravesical instillation of anandamide (50 microm) increased c-fos expression in the spinal cord, which was reduced by capsazepine or by resiniferatoxin pretreatment. These results suggest that anandamide, through activating TRPV1, contributes to the development of hyperreflexia and hyperalgesia during cystitis.

• Insulin induces cobalt uptake in a subpopulation of rat cultured primary sensory neurons.

  Authors: Vivian Sathianathan, António Avelino, Ana Charrua, Peter Santha, Klara Matesz, Francisco Cruz, Istvan Nagy

  The European journal of neuroscience. 12/2003; 18(9):2477-86.

  Previous findings show that both the vanilloid receptor 1 and the insulin receptor are expressed on small primary sensory neurons. As insulin evokes activity in second messengers which could inducePrevious findings show that both the vanilloid receptor 1 and the insulin receptor are expressed on small primary sensory neurons. As insulin evokes activity in second messengers which could induce opening of the vanilloid receptor 1, we examined, by using the cobalt-uptake technique, whether or not insulin can activate cultured rat primary sensory neurons through activating the vanilloid receptor 1. Capsaicin (50, 100 and 500 nm) induced concentration-dependent labelling in primary sensory neurons. Preincubation of cells in insulin (10 micromoles) for 10 min followed by a 2-min wash did not produce significant change in the capsaicin-induced labelling. Coapplication of insulin (10 micromoles) with capsaicin, however, potentiated the 50 and 100 nm capsaicin-evoked staining. Insulin itself also produced cobalt labelling in a concentration-dependent manner. The size-frequency distributions of neurons showing capsaicin- or insulin-induced cobalt accumulation were similar. The insulin-induced cobalt labelling was significantly reduced by the tyrosine kinase inhibitor, tyrphostin AG1024, the vanilloid receptor 1 antagonists, ruthenium red and capsazepine, the protein kinase inhibitor, staurosporine and the phospholipase C inhibitor neomycin. Double immunostaining of cultured primary sensory neurons and sections from dorsal root ganglia revealed that about one-third of the cells coexpress the insulin receptor and vanilloid receptor 1. These findings suggest that insulin activates a subpopulation of primary sensory neurons, probably through phosphorylation- and/or phosphatidylinositol(4,5)biphosphate hydrolysis-evoked activation of the vanilloid receptor 1. Although the insulin-induced activation of vanilloid receptor 1 seems to be a short-lived effect in vitro, in vivo it might play a role in the development of burning pain sensation in hyperinsulinism.