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Search Results: 1 - 10 of 111740 matches for " Robert W Gereau IV "
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Hemispheric lateralization of a molecular signal for pain modulation in the amygdala
Yarimar Carrasquillo, Robert W Gereau IV
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-24
Abstract: The amygdala is a forebrain multinuclear structure with a well-established role in emotional processing [1,2]. Increasing evidence supports the role of the central nucleus of the amygdala (CeA) as a neural modulator of pain perception [3]. Previous work from our laboratory has identified the extracellular signal-regulated kinases (ERKs) as key molecules for the modulation of pain by the CeA in mice [4]. Biochemical experiments showed that ERK is activated in the CeA during persistent inflammation. ERK activation in the CeA was shown to be necessary for inflammation-induced peripheral hypersensitivity because acute pharmacological blockade of ERK activation in this amygdala nucleus reduced inflammation-induced peripheral tactile hypersensitivity. Furthermore, ERK activation in the amygdala was shown to be not only necessary for inflammation-induced peripheral hypersensitivity but also sufficient to induce peripheral tactile hypersensitivity in the absence of tissue injury.Interestingly, the biochemical data from our previous study showed that inflammation-induced ERK activation occurs in the right CeA independent of the side of peripheral inflammation (right or left hindpaw) [4]. These results suggest that modulation of pain by ERK activation in the CeA might be functionally lateralized to the right hemisphere. We tested this hypothesis in the present study by comparing the effects of acute blockade of ERK activation in the right versus the left amygdala when inflammation was induced in the right or the left hind-paw.To induce peripheral inflammation in mice, a 5% formalin solution was injected subcutaneously into the right or the left hind-paw as previously described [4]. Two hours after formalin injection into the hind-paw, the MEK inhibitor U0126 (1.5 nmoles), the inactive structural analog U0124 (1.5 nmoles) or vehicle (50% DMSO/Saline) were infused into the right or the left CeA. Formalin-induced mechanical sensitivity was measured 1 hr after intra-amygdala drug
Targeting Chronic Pain with Epigenetic Drugs: Focus on mGlu2 Receptors
Santina Chiechio,Magda Zammataro,Robert W. Gereau IV,Agata Copani
Molecular and Cellular Pharmacology , 2009,
Abstract: Histone deacetylase (HDAC) enzymes regulate gene expression by affecting chromatin structure and/or the activity of transcription factors. We have recently demonstrated that histone deacetylase inhibitors (HDACIs) behave as epigenetic agents capable of inducing analgesia by up-regulating metabotropic glutamate type 2 (mGlu2) receptors. Specifically, the regulation of mGlu2 receptor expression appears to involve the acetylation of the NF-κB transcription factor. mGlu2 and mGlu3 receptors belong to class II metabotropic glutamate receptors. These receptors are coupled to Gi/o proteins and play an important role in mediating antinociception in a variety of inflammatory and chronic pain models. We have shown that the HDACI-mediated mGlu2 receptor up-regulation occurs in the dorsal horn of the spinal cord and in the dorsal root ganglia, supporting a predominant role for mGlu2 receptors as mediators of analgesia in experimental animal models of chronic pain. We suggest that drugs that increase the expression of mGlu2 receptors, such as HDACIs or acetylating drugs (e.g. L-acetylcarnitine), may be effective in patients with chronic pain that are refractory to conventional analgesics.
Comparative Effects of Heterologous TRPV1 and TRPM8 Expression in Rat Hippocampal Neurons
Devon C. Crawford,Krista L. Moulder,Robert W. Gereau IV,Gina M. Story,Steven Mennerick
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008166
Abstract: Heterologous channel expression can be used to control activity in select neuronal populations, thus expanding the tools available to modern neuroscience. However, the secondary effects of exogenous channel expression are often left unexplored. We expressed two transient receptor potential (TRP) channel family members, TRPV1 and TRPM8, in cultured hippocampal neurons. We compared functional expression levels and secondary effects of channel expression and activation on neuronal survival and signaling. We found that activation of both channels with appropriate agonist caused large depolarizing currents in voltage-clamped hippocampal neurons, exceeding the amplitude responses to a calibrating 30 mM KCl stimulation. Both TRPV1 and TRPM8 currents were reduced but not eliminated by 4 hr incubation in saturating agonist concentration. In the case of TRPV1, but not TRPM8, prolonged agonist exposure caused strong calcium-dependent toxicity. In addition, TRPV1 expression depressed synaptic transmission dramatically without overt signs of toxicity, possibly due to low-level TRPV1 activation in the absence of exogenous agonist application. Despite evidence of expression at presynaptic sites, in addition to somatodendritic sites, TRPM8 expression alone exhibited no effects on synaptic transmission. Therefore, by a number of criteria, TRPM8 proved the superior choice for control over neuronal membrane potential. This study also highlights the need to explore potential secondary effects of long-term expression and activation of heterologously introduced channels.
Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception
Lara W Crock, Kristina M Stemler, David G Song, Philip Abbosh, Sherri K Vogt, Chang-Shen Qiu, H Henry Lai, Indira U Mysorekar, Robert W Gereau IV
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-20
Abstract: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice.Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.Interstitial cystitis/painful bladder syndrome (IC/PBS) is a serious and painful condition of unknown etiology that affects 3-6% of women in the United States [1,2]. The major clinical symptom of IC/PBS is pain upon bladder filling (distention) leading to urinary frequency and urinary urgency [3]. The current available treatments are often ineffective and do not treat the underlying pathology. Rodent bladder-injury models that induce some of the symptoms observed in IC/PBS have been used to evaluate potential treatments for IC/PBS [4-9]. One injury model, bacterial cystitis (urinary tract infection, UTI) is known to cause a similar constellation of symptoms as observed in IC/PBS (i.e. urinary frequency and urgency [10-12]). In addition, bacterial cystitis can be modeled in rodents through bladder exposure to uropathogenic Escherichia Coli (UPEC) [13,14]. Bladder infections due to UPEC are responsible for approximately 80% of UTIs in otherwise healthy women [15,16]. Understanding the underlying molecular mechanisms of both non-inflammatory bladder pain and inflammatory bladder pain due to UPEC infection could lead to the development of novel treatments for painful bladder infections as well as for IC/PBS and po
The Effects of Tail Biopsy for Genotyping on Behavioral Responses to Nociceptive Stimuli
Maria Elena P. Morales, Robert W. Gereau
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006457
Abstract: Removal of a small segment of tail at weaning is a common method used to obtain tissue for the isolation of genomic DNA to identify genetically modified mice. When genetically manipulated mice are used for pain research, this practice could result in confounding changes to the animals' responses to noxious stimuli. In this study, we sought to systematically investigate whether tail biopsy representative of that used in standard genotyping methods affects behavioral responses to a battery of tests of nociception. Wild-type littermate C57BL/6J and 129S6 female and male mice received either tail biopsies or control procedural handling at Day 21 after birth and were then tested at 6–9 weeks for mechanical and thermal sensitivity. C57BL/6J mice were also tested in the formalin model of inflammatory pain. In all tests performed (von Frey, Hargreaves, modified Randall Selitto, and formalin), C57BL/6J tail-biopsied animals' behavioral responses were not significantly different from control animals. In 129S6 animals, tail biopsy did not have a significant effect on behavioral responses in either sex to the von Frey and the modified Randall-Selitto tests of mechanical sensitivity. Interestingly, however, both sexes exhibited small but significant differences between tail biopsied and control responses to a radiant heat stimulus. These results indicate that tail biopsy for genotyping purposes has no effect on nocifensive behavioral responses of C57BL/6J mice, and in 129S6 mice, causes only a minor alteration in response to a radiant heat stimulus while other nocifensive behavioral responses are unchanged. The small effect seen is modality- and strain-specific.
A Novel Behavioral Assay for Measuring Cold Sensation in Mice
Daniel S. Brenner, Judith P. Golden, Robert W. Gereau
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039765
Abstract: Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia.
mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists
Magda Zammataro, Santina Chiechio, Michael C Montana, Anna Traficante, Agata Copani, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-6
Abstract: In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors.Metabotropic glutamate (mGlu) receptors are considered promising targets in the treatment of chronic pain. All mGlu receptor subtypes (mGlu1-8), except mGlu6, are widely distributed along the pain neuraxis, and modulate cellular mechanisms of nociceptive sensitization that underlie the development of chronic pain [1-3]. We and others have focused on the role of group-II mGlu receptors (mGlu2 and mGlu3), which are coupled to Gi proteins and depress pain transmission at synapses between primary afferent fibers and second order sensory neurons in the dorsal horn of the spinal cord [4,5]. mG
Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-κB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine
Santina Chiechio, Agata Copani, Laura De Petris, Maria Elena P Morales, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-20
Abstract: Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) induces antinociception in several pain models in rodents [1-5]. Consistent with these studies, we have shown that L-acetylcarnitine (LAC), a drug clinically effective in the treatment of neuropathic pain of various origins [6-9], up-regulates the expression of mGlu2 in the dorsal root ganglia (DRG) and in the dorsal horn (DH) of the spinal cord [10,11]. This has challenged the previous view that LAC increases pain thresholds and relieves neuropathic pain by enhancing brain acetylcholine synthesis [12] or by increasing the trophism of peripheral nerves [13,14]. Consistent with the "mGlu2 hypothesis of LAC-induced analgesia," the mGlu2/3 receptor antagonist, LY341495, prevents LAC-induced analgesia in rodents [10]. Interestingly, LAC selectively enhances the expression of mGlu2 receptors and has no effect on the expression of mGlu3 receptors [10,15], although these two receptor subtypes are highly homologous and share similar functions in the CNS [16]. This suggests that the expression of mGlu2 and mGlu3 is differentially regulated and that unraveling the nature of this difference may lead to the identification of new targets for the treatment of neuropathic pain.Analysis of the 5'-region upstream of the coding sequence of the human GRM2 gene (encoding mGlu2) [GenBank: AB045011], using the Transcription Factor Binding Sites Database TRANSFACT and TFSEARCH, revealed the presence of many potential regulatory elements for transcription factors of the NF-κB family, including p50 and p65/Rel-A, and for the coactivator p300. In contrast, only one binding site for the NF-κB family protein, c-Rel, and no binding sites for p65/RelA and p300 have been described in the putative promoter region of the human GRM3 gene encoding mGlu3 [17]. Hence, we focused on the NF-κB pathway in the search for mechanisms that account for the selective effect of LAC on mGlu2 expression.NF-κB consists of transcription factor
Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK)
Farzana Karim, Hui-Juan Hu, Hita Adwanikar, David Kaplan, Robert W Gereau
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-2
Abstract: Formalin-induced second phase spontaneous pain behaviors as well as thermal hyperalgesia measured 1 – 3 hours post-formalin were significantly reduced in the DN MEK mice when compared to their wild type littermate controls. In addition, spinal ERK phosphorylation following formalin injection was significantly reduced in the DN MEK mice. This was not due to a reduction of the number of unmyelinated fibers in the periphery, since these were almost double the number observed in wild type controls. Further examination of the effects of suppression of MEK function on a downstream target of ERK phosphorylation, the A-type potassium channel, showed that the ERK-dependent modulation of the A-type currents is significantly reduced in neurons from DN MEK mice compared to littermate wild type controls.Our results demonstrate that the neuronal MEK-ERK pathway is indeed an important intracellular cascade that is associated with formalin-induced inflammatory pain and thermal hyperalgesia.Extracellular signal-regulated kinases (ERKs) belong to a cascade that is part of a phosphorelay system composed of three sequentially activated kinases regulated by phosphorylation. Initiation of this cascade occurs via multiple mechanisms which ultimately activate raf kinases. Activated raf phosphorylates MEK which phosphorylates ERK1 and ERK2 on tyrosine and threonine residues. Extracellular signal-regulated kinases are involved in the regulation of meiosis and mitosis, and in differentiated cells, ERKs integrate a wide variety of postmitotic functions [1-3]. Within the past decade, numerous studies in rodents have elucidated the role of ERKs in nociceptive plasticity. ERK activation is activity-dependent, and occurs following noxious stimulation [4,5]. The role of ERK in nociceptive plasticity has been extensively studied in the spinal cord and dorsal root ganglia, two important sites of nociceptive sensitization [6-9]. In addition to different types of noxious stimuli, high intensity electri
翼龙类和驰龙类尾的前关节突和脉弧棒的趋同演化及翼龙类和鸟类尾部肌肉退化的平行模式
W. Scott PERSONS, IV
地球学报 , 2010, DOI: 10.3975/cagsb.2010.s1.28
Abstract: Thecaudalmorphologyofdromaeosauriddinosaursandmost“rhamphorhynchoid”pterosaursisastrikingexampleofconvergentevolution.Inbothgroups,allbutthemostanteriorfivetosevencaudalvertebraehavepostzygopophysesthatareelongate,equalingorexceedingthecorrespondingcentrainlength,andhavebifurcatingrod-shapedprezygopophysesthatextendasmuchasseventimesthelengthofthecorrespondingcentra.
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