Journal club 2014-06-13

By
Neuron. 2014 May 7;82(3):573-86. doi: 10.1016/j.neuron.2014.02.046. Epub 2014 Apr 10.

Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.

Kardon AP1, Polgár E2, Hachisuka J1, Snyder LM1, Cameron D2, Savage S2, Cai X1, Karnup S1, Fan CR3, Hemenway GM3, Bernard CS3, Schwartz ES4,Nagase H5, Schwarzer C6, Watanabe M7, Furuta T8, Kaneko T8, Koerber HR1, Todd AJ9, Ross SE10.

Abstract

Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5(-/-) mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.

mmc2
Filename : mmc2.pdf (5 MB)
Caption :

Journal Club 2014-05-24

By
Acta Derm Venereol. 2014 Mar 7. doi: 10.2340/00015555-1834. [Epub ahead of print]

Surfactant-induced Chronic Pruritus: Role of L-Histidine Decarboxylase Expression and Histamine Production in Epidermis.

4143
Filename : 4143.pdf (408 KB)
Caption :

Abstract

Shampoo and cleansers containing anionic surfactants including sodium dodecyl sulphate (SDS) often causepruritus in humans. Daily application of 1-10% SDS for 4 days induced hind-paw scratching (an itch-related behaviour) in a concentration-dependent manner, and 10% SDS also caused dermatitis, skin dryness, barrier disruption, and an increase in skin surface pH in mice. SDS-induced scratching was inhibited by the opioid receptor antagonist naloxone and the H1 histamine receptor antagonist terfenadine. Mast-cell deficiency did not inhibit SDS-induced scratching, although it almost completely depleted histamine in the dermis. Treatment with SDS increased the histamine content of the epidermis, but not that of the dermis. SDS treatment increased the gene expression and post-translation processing of L-histidine decarboxylase in the epidermis. The present results suggest that repeated application of SDS induces itch through increased production of epidermal histamine, which results from an increase in the gene expression and post-translation processing of L-histidine decarboxylase.

PMID: 24603881

Journal Club 2014-05-09

By
Mol Brain. 2014 Apr 3;7(1):25. doi: 10.1186/1756-6606-7-25.

Extracellular signal-regulated kinase (ERK) activation is required for itch sensation in the spinal cord.

1756-6606-7-25
Filename : 1756-6606-7-25.pdf (3 MB)
Caption :

Abstract

BACKGROUND:

Itch, chronic itch in particular, can have a significant negative impact on an individual’s quality of life. However, the molecular mechanisms underlying itch processing in the central nervous system remain largely unknown.

RESULTS:

We report here that activation of ERK signaling in the spinal cord is required for itch sensation. ERK activation, as revealed by anti-phosphorylated ERK1/2 immunostaining, is observed in the spinal dorsal horn of mice treated with intradermal injections of histamine and compound 48/80 but not chloroquine or SLIGRL-NH2, indicating that ERK activation only occurs in histamine-dependent acute itch. In addition, ERK activation is also observed in 2, 4-dinitrofluorobenzene (DNFB)-induced itch. Consistently, intrathecal administration of the ERK phosphorylation inhibitor U0126 dramatically reduces the scratching behaviors induced by histamine and DNFB, but not by chloroquine. Furthermore, administration of the histamine receptor H1 antagonist chlorpheniramine decreases the scratching behaviors and ERK activation induced by histamine, but has no effect on DNFB-induced itch responses. Finally, the patch-clamp recording shows that in histamine-, chloroquine- and DNFB-treated mice the spontaneous excitatory postsynaptic current (sEPSC) of dorsal horn neurons is increased, and the decrease of action potential threshold is largely prevented by bathing of U0126 in histamine- and DNFB-treated mice but not those treated with chloroquine.

CONCLUSION:

Our results demonstrate a critical role for ERK activation in itch sensation at the spinal level.

Journal Club 2014-04-25

By

Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and -Independent Itch

Abstract

Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt−/− mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020559

Journal Club 2014-04-11

By

BEHAVIORAL MODEL OF ITCH, ALLOKNESIS, PAIN AND ALLODYNIA IN THE LOWER HINDLIMB AND CORRELATIVE RESPONSES
OF LUMBAR DORSAL HORN NEURONS IN THE MOUSE

T. AKIYAMA, M. NAGAMINE, M. I. CARSTENS AND E. CARSTENS *

University of California, Davis, Department of Neurobiology, Physiology & Behavior, 1 Shields Avenue, Davis, CA 95616, USA

1-s2.0-S0306452214001018-main

Abstract—We have further developed a behavioral model of itch and pain in the lower hindlimb (calf) originally reported by LaMotte et al. (2011) that allows comparisons with responses of lumbar dorsal horn neurons to pruritic and noxious stimuli. Intradermal (id) microinjection of the prurit- ogens histamine, SLIGRL-NH2 (agonist of PAR-2 and MrgprC11) and chloroquine (agonist of MrgprA3) into the calf of the lower limb elicited significant biting and a small amount of licking directed to the injection site, over a 30- min time course. Following id injection of histamine, low-threshold mechanical stimuli reliably elicited discrete episodes of biting (alloknesis) over a longer time course; significantly less alloknesis was observed following id injec- tion of SLIGRL-NH2. Capsaicin injections elicited licking but little biting. Following id injection of capsaicin, low-thresh- old mechanical stimuli elicited discrete hindlimb flinches (allodynia) over a prolonged (>2 h) time course. In single- unit recordings from superficial lumbar dorsal horn neurons, low-threshold mechanically evoked responses were significantly enhanced, accompanied by receptive field expansion, following id injection of histamine in histamine- responsive neurons. This was not observed in histamine- insensitive neurons, or following id injection of saline or SLIGRL-NH2, regardless of whether the latter activated the neuron or not. These results suggest that itch-responsive neurons are selectively sensitized by histamine but not SLI- GRL-NH2 to account for alloknesis. The presently described ‘‘calf’’ model appears to distinguish between itch- and pain- related behavioral responses, and provides a basis to inves- tigate lumbar spinal neural mechanisms underlying itch, alloknesis, pain and allodynia. Ó 2014 Published by Elsevier Ltd. on behalf of IBRO.

Key words: itch, alloknesis, pain, allodynia, scratching, dor- sal horn neuron.

Journal Club 2014-04-04

By

Structure of the TRPV1 ion channel determined by electron cryo-microscopy

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4 Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane segments 5–6 (S5–S6) and the intervening pore loop, which is flanked by S1–S4 voltage-sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with a short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including amino-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

Liao et al_2013_Structure of the TRPV1 ion channel determined by electron cryo-microscopy

Journal Club 2014-03-28

By

TRPV3 is a calcium-permeable temperature-sensitive cation channel

12077604-Nature-2002-TRPV3 is a calcium-permeable temperature-sensitive

Haoxing Xu*†, I. Scott Ramsey*†, Suhas A. Kotecha*†,
Magdalene M. Moran‡, Jayhong A. Chong*, Deborah Lawson§, Pei Ge§, Jeremiah Lilly§, Inmaculada Silos-Santiago§, Yu Xie§,
Peter S. DiStefano§k, Rory Curtis§k & David E. Clapham*

* Howard Hughes Medical Institute, Children’s Hospital, Harvard Medical School, Enders 1309, 320 Longwood Avenue, Boston, Massachusetts 02115, USA ‡ Program in Neuroscience, Harvard Medical School, Goldenson Building B2-228, 220 Longwood Avenue, Boston, Massachusetts 02115, USA
§ Millennium Pharmaceuticals Inc., 75 Sidney Street, Cambridge, Massachusetts 02139, USA
† These authors contributed equally to this work

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 8C; TRPV1 (ref. 1)), noxious heat (>52 8C; TRPV2 (ref. 2)), and cooling (< 22 8C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between ,22 8C and 40 8C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 228C to 408C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cat- ionic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hyster- esis on heating and cooling5–10. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1.

Journal Club 2014-03-22

By

Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1

nature02282

Sven-Eric Jordt1, Diana M. Bautista1, Huai-hu Chuang1,
David D. McKemy1, Peter M. Zygmunt3, Edward D. Ho ̈ gesta ̈ tt3, Ian D. Meng2* & David Julius1

1Department of Cellular and Molecular Pharmacology and 2Department of Neurology, University of California, San Francisco, California 94143-2140, USA 3Department of Clinical Pharmacology, Institute of Laboratory Medicine,
Lund University Hospital, SE-221 85 Lund, Sweden

* Present address: Department of Physiology, College of Osteopathic Medicine, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, USA ………………………………………………………………………………………………………………………………………………………..

Wasabi, horseradish and mustard owe their pungency to iso- thiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust

1,2 hypersensitivity to thermal and mechanical stimuli . Despite

their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by D9-tetrahydrocannabinol (THC), the psycho- active component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the transient receptor potential (TRP) ion channel family recently implicated in the detection of noxious cold3,4. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors5–8.

Journal Club 2014.03.05

By

Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model ofinflammatory itch and pain

Lintao Qu,1,* Ni Fan,1,2,* Chao Ma,1,3 Tao Wang,1,3 Liang Han,4 Kai Fu,1 Yingdi Wang,5 Steven G. Shimada,1 Xinzhong Dong4 and Robert H. LaMotte1

  1. 1  Department of Anaesthesiology, Yale University School of Medicine, New Haven, CT, 06520, USA
  2. 2  Guangzhou Brain Hospital, the Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China 510370
  3. 3 InstituteofBasicMedicalSciences,Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Department of Anatomy, Histology and Embryology, Beijing, China
  4. 4  Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
  5. 5  Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA

*These authors contributed equally to this work.

Correspondence to: Robert H. LaMotte, Ph.D.,
Department of Anaesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
E-mail: robert.lamotte@yale.edu

Brain-2014-Qu-brain_awu007

Itch is a common symptom of diseases of the skin but can also accompany diseases of other tissues including the nervous system. Acute itch from chemicals experimentally applied to the skin is initiated and maintained by action potential activity in a subset of nociceptive neurons. But whether these pruriceptive neurons are active or might become intrinsically more excitable under the pathological conditions that produce persistent itch and nociceptive sensations in humans is largely unexplored. Recently, two distinct types of cutaneous nociceptive dorsal root ganglion neurons were identified as responding to pruritic chemicals and playing a role in itch sensation. One expressed the mas-related G-coupled protein receptor MRGPRA3 and the other MRGPRD (MRGPRA3+ and MRGPRD+ neurons, respectively). Here we tested whether these two distinct pruriceptive nociceptors exhibited an enhanced excitability after the development of contact hypersensitivity, an animal model of allergic contact dermatitis, a common pruritic disorder in humans. The characteristics of increased excitability of pruriceptive neurons during this disorder may also pertain to the same types of neurons active in other pruritic diseases or pathologies that affect the nervous system and other tissues or organs. We found that challenging the skin of the calf of the hind paw or the cheek of previously sensitized mice with the hapten, squaric acid dibutyl ester, produced symptoms of contact hypersensitivity including an increase in skin thickness and site-directed spontaneous pain-like (licking or wiping) and itch-like (biting or scratching) behaviours. Ablation of MRGPRA3+ neurons led to a significant reduction in spontaneous scratching of the hapten-challenged nape of the neck of previously sensitized mice. In vivo, electrophysiological recordings revealed that MRGPRA3+ and MRGPRD+ neurons innervating the hapten-challenged skin exhibited a greater incidence of spontaneous activity and/or abnor- mal after-discharges in response to mechanical and heat stimuli applied to their receptive fields compared with neurons from the vehicle-treated control animals. Whole-cell recordings in vitro showed that both MRGPRA3+ and MRGPRD+ neurons from hapten-challenged mice displayed a significantly more depolarized resting membrane potential, decreased rheobase, and greater number of action potentials at twice rheobase compared with neurons from vehicle controls. These signs of neuronal hyper- excitability were associated with a significant increase in the peak amplitude of tetrodotoxin-sensitive and resistant sodium currents. Thus, the hyperexcitability of MRGPRA3+ and MRGPRD+ neurons, brought about in part by enhanced sodium currents, may contribute to the spontaneous itch- and pain-related behaviours accompanying contact hypersensitivity and/or other inflammatory diseases in humans.

Keywords: itch; pain; MRGPRA3; MRGPRD; allergic contact dermatitis
Abbreviations: CHS = contact hypersensitivity; GFP = green fluorescent protein; SADBE = squaric acid dibutyl ester;

TTX = tetrodotoxin

Scroll to Top