Journal club 2014.02.13.

Cortical GluK1 kainate receptors modulate scratching in adult mice

Journal of Neurochemistry | 2013 | 126 | 636-650

Kaori Yamada and Min Zhuo

Abstract

Recent investigations into the mechanisms mediating itch transmission have focused on spinal mechanisms, whereas few studies have investigated the role of the cerebral cortex in itch-related behaviors. Human imaging studies show that several cortical regions are active in correspondence with itch, including the anterior cingulate cortex (ACC). We present here evidence of cortical modulation of pruritogen-induced scratch- ing behavior. We combine pharmacological, genetic, and electrophysiological approaches to show that cortical GluK1- containing kainate (KA) receptors are involved in scratching

induced by histamine and non-histamine-dependent itching stimuli. We further show that scratching corresponds with enhanced excitatory transmission in the ACC through KA receptor modulation of inhibitory circuitry. In addition, we found that inhibiting GluK1-containing KA receptors in the ACC also reduced behavioral nociceptive responses induced by forma- lin. Our results reveal a new role of the cortex in pruritogen- induced scratching.

Keywords: cortex, glutamatergic transmission, inhibitory trans- mission, itch, kainate receptors, scratching.
J. Neurochem. (2013) 126, 636–650.

Journal club 2014.01.29.

By onlynice20

Distinct Expression of Mas1-Related G-Protein-Coupled Receptor B4 in Dorsal Root and Trigeminal Ganglia—Implications for Altered Behaviors in Acid-Sensing Ion Channel 3-Deficient Mice

Ya-Han Huang & Chin-Yu Chang & Chih-Cheng Chen & Chih-Dong Yang & Wei-Hsin Sun

Received: 26 February 2013 / Accepted: 8 July 2013 / Published online: 31 July 2013 # Springer Science+Business Media New York 2013

art%3A10.1007%2Fs12031-013-0070-0

Abstract

Mas1-related G-protein-coupled receptors (Mrgprs), comprising more than 50 distinct members, are specifically expressed in primary sensory neurons. Reflecting the diversity and specificity of stimuli they detect, Mrgprs are involved in pain, touch, and itch-related behaviors. Sensory–neuron-specif- ic acid-sensing ion channel 3 (ASIC3) is essential for touch and inflammatory pain, but mice lacking ASIC3 have complex behavioral alterations in various modalities of pain and touch. To understand whether Mrgprs are involved in complex behav- ioral alterations found in ASIC3-deficient mice, we examined Mrgpr gene expression in ASIC3−/− mice. Only MrgprB4 expression has shown significant change. MrgprB4 expression was increased in ASIC3−/− dorsal root ganglia (DRG) but decreased in ASIC3−/− trigeminal ganglia. The distinct alter- ations in DRG and trigeminal ganglia imply that MrgprB4 could have multiple functions. Given that MrgprB4 is expressed in neurons that may detect gentle touch and that ASIC3−/− mice have altered sensitivity of mechanoreceptors for light touch, the expression change of MrgprB4 is more likely related to the altered touch behaviors of ASIC3−/− mice.

Keywords

Dorsal root ganglion . Trigeminal ganglion . Mas1-related G-protein-coupled receptor B4 . ASIC3 . Nociceptors

Journal Club 2014.01.16

By onlynice20

Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch

Tasuku Akiyama a, Mitsutoshi Tominaga b, Kenji Takamori b, Mirela Iodi Carstens a, E. Carstens a,⇑ a Department of Neurobiology, Physiology & Behavior, University of California, Davis, CA, USA

b Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Chiba 279-0021, Japan

1-s2.0-S0304395913005083-main

abstract

We investigated roles for substance P (SP), gastrin-releasing peptide (GRP), and glutamate in the spinal neurotransmission of histamine-dependent and -independent itch. In anesthetized mice, responses of single superficial dorsal horn neurons to intradermal (i.d.) injection of chloroquine were partially reduced by spinal application of the a-amino-3-hydroxy-5-methyl-4-isoxazole proprionate acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Co-application of CNQX plus a neurokinin-1 (NK-1) antagonist produced stronger inhibition, while co-application of CNQX, NK-1, and GRP receptor (GRPR) antagonists completely inhibited firing. Nociceptive-specific and wide dynamic range-type neu- rons exhibited differential suppression by CNQX plus either the GRPR or NK-1 antagonist, respectively. Neuronal responses elicited by i.d. histamine were abolished by CNQX alone. In behavioral studies, indi- vidual intrathecal administration of a GRPR, NK-1, or AMPA antagonist each significantly attenuated chlo- roquine-evoked scratching behavior. Co-administration of the NK-1 and AMPA antagonists was more effective, and administration of all 3 antagonists abolished scratching. Intrathecal CNQX alone prevented histamine-evoked scratching behavior. We additionally employed a double-label strategy to investigate molecular markers of pruritogen-sensitive dorsal root ganglion (DRG) cells. DRG cells responsive to his- tamine and/or chloroquine, identified by calcium imaging, were then processed for co-expression of SP, GRP, or vesicular glutamate transporter type 2 (VGLUT2) immunofluorescence. Subpopulations of chloro- quine- and/or histamine-sensitive DRG cells were immunopositive for SP and/or GRP, with >80% immu- nopositive for VGLUT2. These results indicate that SP, GRP, and glutamate each partially contribute to histamine-independent itch. Histamine-evoked itch is mediated primarily by glutamate, with GRP play- ing a lesser role. Co-application of NK-1, GRP, and AMPA receptor antagonists may prove beneficial in treating chronic itch.

journal 2014-01-02

By somi2388

Pharmacological Blockade of TRPM8 Ion Channels Alters Cold and Cold Pain Responses in Mice

.journal.pone.0025894

Abstract

TRPM8 (Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybenzyl(2-aminoethyl)carbamate)which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo

Journal Club 2013/12/26

By onlynice20

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1
Viola Spahn, Christoph Stein and Christian Zöllner

Mol Pharmacol-2013-Spahn-mol.113.088997

Abstract

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective ligand-gated cation channel responding to noxious heat, protons, and chemicals like capsaicin. TRPV1 is expressed in sensory neurons and plays a critical role in pain associated with tissue injury, inflammation or nerve lesions. Transient Receptor Potential Ankyrin 1 (TRPA1) is co- expressed with TRPV1. It is activated by compounds that cause a burning sensation (e.g. mustard oil) and, indirectly, by components of the inflammatory milieu eliciting nociceptor excitation and pain hypersensitivity. Previous studies indicate an interaction of TRPV1 and TRP A1 signaling pathways. Here we sought to examine the molecular mechanisms underlying such interactions in nociceptive neurons. We first excluded physical interactions of both channels using radioligand binding studies. By microfluorimetry, electrophysiological experiments, cAMP measurements, and site-directed mutagenesis we found a sensitization of TRPV1 after TRPA1 stimulation with mustard oil in a calcium- and cAMP/PKA-dependent manner. TRPA1 stimulation enhanced TRPV1 phosphorylation via the putative PKA phosphorylation site serine 116. We also detected calcium-sensitive increased TRPV1 activity after TRPA1 activation in dorsal root ganglion (DRG) neurons. The inhibition of TRPA1 by HC-030031 after its initial stimulation and the calcium-insensitive TRPA1 mutant D477A still showed increased capsaicin-induced TRPV1 activity excluding an additive TRPA1 current after TRPV1 stimulation. Our study shows sensitization of TRPV1 via activation of TRPA1, which involves adenylyl cyclase, increased cAMP, subsequent translocation and activation of PKA, and phosphorylation of TRPV1 at PKA phosphorylation residues. This suggests that cross-sensitization of TRP channels contributes to enhanced pain sensitivity in inflamed tissues.

journal 2013-12-13

By somi2388

1664.full

Journal club 2013-11-29

By onlynice20

Chronic itch development in sensory neurons requires BRAF signaling pathways

JCI70528

Zhong-Qiu Zhao,1,2 Fu-Quan Huo,1,2 Joseph Jeffry,1,2 Lori Hampton,3 Shadmehr Demehri,4,5 Seungil Kim,1 Xian-Yu Liu,1,2 Devin M. Barry,1,5 Li Wan,1,6 Zhong-Chun Liu,1,2 Hui Li,1,7 Ahu Turkoz,4 Kaijie Ma,8 Lynn A. Cornelius,1,5 Raphael Kopan,4 James F. Battey Jr.,9
Jian Zhong,8,10 and Zhou-Feng Chen1,2,4

1Center for the Study of Itch and 2Departments of Anesthesiology and Psychiatry, Washington University School of Medicine Pain Center,
St. Louis, Missouri, USA. 3Office of Laboratory Animal Welfare, NIH, Bethesda, Maryland, USA. 4Department of Developmental Biology and 5Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 6Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
7Department of Anatomy, Histology, and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an, China. 8Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York, USA.
9National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.
10Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York, USA.

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAFNav1.8 mice). We found that constitutive BRAF pathway activation in BRAFNav1.8 mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAFNav1.8 mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excit- ability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for main- taining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.

Journal club 2013-11-22

By Won-Sik Shim

: Filename : 1-s2-0-s0014299912003585-main.pdf (401 KB)
Caption :

Eur J Pharmacol. 2012 Jul 5;686(1-3):16-21. doi: 10.1016/j.ejphar.2012.04.024. Epub 2012 Apr 21.

Cathepsin E induces itch-related response through the production of endothelin-1 in mice.

Andoh T, Yoshida T, Lee JB, Kuraishi Y.

Source

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Japan.

Abstract

This study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, an itch-associated response, of the injection site. This action was inhibited by the aspartic protease inhibitor pepstatin A, the endothelin ET(A) receptor antagonist BQ-123, and the opioid receptor antagonists naltrexone and naloxone, but not by the H(1) histamine receptor antagonist terfenadine, the proteinase-activated receptor-2 antagonist FSLLRY-NH(2), or mast cell deficiency. Pepstatin A inhibited scratching induced by intradermal injection of the mast-cell degranulator compound 48/80, but not by tryptase, a mast-cell mediator. An intradermal injection of cathepsin E increased endothelin-1 levels in the skin at the injection site. Preproendothelin-1 mRNA was present in primary cultures of keratinocytes, and immunohistochemistry using an antibody recognizing endothelin-1 and big-endothelin-1 revealed immunoreactivity in the epidermis, especially in the prickle and granular cell layers, but not in the basal cell layer. These results suggest that cathepsin E is an endogenous itch inducer, and that its action is mediated at least in part by the production of endothelin-1 in the epidermis.

PMID:: 22546226; [PubMed – indexed for MEDLINE]

journal 2013-11-15

By somi2388

all2854

The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.

Ohsawa Y, Hirasawa N.

Source

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. yuusuke_oosawa@pharm.kissei.co.jp

Abstract

BACKGROUND:

Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice.

METHODS:

Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes.

RESULTS:

JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes.

CONCLUSION:

Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

Journal club 2013-11-15

By Won-Sik Shim

: Filename : all2854.pdf (808 KB)
Caption :

Allergy. 2012 Aug;67(8):1014-22. doi: 10.1111/j.1398-9995.2012.02854.x. Epub 2012 Jun 12.

The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.

Ohsawa Y, Hirasawa N.

Source

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. yuusuke_oosawa@pharm.kissei.co.jp

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSION:

Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

PMID:: 22686688; [PubMed – indexed for MEDLINE]