Journal club 2013-05-31

The Cells and Circuitry for Itch Responses in Mice

Santosh K. Mishra and Mark A. Hoon*

www.sciencemag.org_content_340_6135_968.full

www.sciencemag.org_content_suppl_2013_05_23_340.6135.968.DC1_Mishra-SM

Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb−/− mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb−/− mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor–expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next
two stages of this dedicated neuronal pathway.

Journal club 2013-05-24

By somi2388

1-s2.0-S0306452212009220-main

Cross-sensitization of histamine-independent itch in mouse primary sensory neurons

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

Accepted 8 September 2012

Available online 19 September 2012

http://dx.doi.org/10.1016/j.neuroscience.2012.09.019, How to Cite or Link Using DOI

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Abstract

Overexpression of pruritogens and their precursors may contribute to the sensitization of histamine-dependent and –independent itch-signaling pathways in chronic itch. We presently investigated self- and cross-sensitization of scratching behavior elicited by various pruritogens, and their effects on primary sensory neurons. The MrgprC11 agonist BAM8-22 exhibited self- and reciprocal cross-sensitization of scratching evoked by the protease-activated receptor-2 (PAR-2) agonist SLIGRL. The MrgprA3 agonist chloroquine unidirectionally cross-sensitized BAM8-22-evoked scratching. Histamine unidirectionally cross-sensitized scratching evoked by chloroquine and BAM8-22. SLIGRL unidirectionally cross-sensitized scratching evoked by chloroquine. Dorsal root ganglion (DRG) cells responded to various combinations of pruritogens and algogens. Neither chloroquine, BAM8-22 nor histamine had any effect on responses of DRG cell responses to subsequently applied pruritogens, implying that their behavioral self- and cross-sensitization effects are mediated indirectly. SLIGRL unilaterally cross-sensitized responses of DRG cells to chloroquine and BAM8-22, consistent with the behavioral data. These results indicate that unidirectional cross-sensitization of histamine-independent itch-signaling pathways might occur at a peripheral site through PAR-2. PAR-2 expressed in pruriceptive nerve endings is a potential target to reduce sensitization associated with chronic itch.

Journal club 2013-05-10

By onlynice20

The TGR5 receptor mediates bile acid– induced itch and analgesia

64551

Farzad Alemi,1 Edwin Kwon,1 Daniel P. Poole,2 TinaMarie Lieu,3 Victoria Lyo,1 Fiore Cattaruzza,1 Ferda Cevikbas,4 Martin Steinhoff,4 Romina Nassini,5 Serena Materazzi,5 Raquel Guerrero-Alba,6 Eduardo Valdez-Morales,6 Graeme S. Cottrell,7 Kristina Schoonjans,8 Pierangelo Geppetti,5 Stephen J. Vanner,6 Nigel W. Bunnett,3 and Carlos U. Corvera1

1Department of Surgery, UCSF, San Francisco, California, USA. 2Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia. 3Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia. 4Department of Dermatology, UCSF, San Francisco, California, USA. 5Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. 6Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada. 7Department of Pharmacy and Pharmacology, The University of Bath, Bath, United Kingdom. 8Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, School of Life Sciences, Lausanne, Switzerland.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symp- toms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cho- lestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neu- rons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine- enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide– and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.