Report from the 4Th International Workshop for the Study of Itch Gil Yosipovitch1 and E

MEETING REPORT

Report from the 4th International Workshop for the Study of Itch Gil Yosipovitch1 and E. Carstens2 Journal of Investigative Dermatology (2008), 128, 256–257. doi:10.1038/sj.jid.5701218

The 4th International Workshop for cal stimuli can evoke itch, prompting a brain imaging technique—arterial spin the Study of Itch* was held 9–11 renewed and timely effort to discover labeling—that appears better suited September 2007 in San Francisco, new itch fibers. Collaborating neurosci- to evaluate itch than functional mag- California. For the first time, the meet- entists from Yale, John Hopkins, and the netic resonance imaging or positron ing was sponsored in part by a grant University of Minnesota were able to emission tomography. Atopic eczema from the National Institute of Arthritis demonstrate the existence of novel pop- patients suffering from chronic itch and Musculoskeletal and Skin Diseases ulations of peripheral afferent fibers, as exhibited significant differences from and the Office of Rare Diseases of the well as spinothalamic tract neurons in healthy control subjects in the distribu- National Institutes of Health. Also for primates, that respond to cowhage, the tion of brain areas that were active both the first time, the meeting was held “velvet” bean plant whose pods con- under baseline conditions and during under the auspices of the International tain spicules that were demonstrated histamine-evoked itch. Forum for the Study of Itch (IFSI). to induce cutaneous itch more than Organized by Earl and Mirela Carstens, 50 years ago by Walter Shelly. Mathias Molecular mechanisms of itch and the meeting was attended by more Ringkamp (John Hopkins University, genetic models than 130 scientists and physicians Baltimore, MD) presented data from Zhou Feng Chen (Washington from throughout the world. The work- human psychophysical studies demon- University, St. Louis, MO) presented shop covered a vast range of topics, strating that cowhage spicules induced findings using a differential screening including the neurophysiology of itch itch without flare. Topical antihista- technique to identify gastrin-releasing in humans and animals, molecular mines did not inhibit this itch, but cap- peptide receptor (GRPR) as a candidate mechanisms of itch, neurogenic inflam- saicin, a C-fiber depleter, did. Glenn neurotransmitter in the superficial spi- mation, and pharmacology of anti- Giesler and colleagues at the University nal dorsal horn that is involved in itch pruritics. Clinical aspects were well of Minnesota (Minneapolis) presented transmission. GRPR is a G protein–cou- covered, and there was a lively discus- new data on a subpopulation of identi- pled receptor derived from the bombe- sion of itch definitions. Other topics fied spinothalamic tract (STT) neurons sin family. Mutant mice lacking GRPR included clinical research on the epide- in primates that were activated by cow- exhibited significantly less scratching miology and pathophysiology of itch in hage over a time course matching that behavior in response to three pruritic systemic disease, neuropathic itch, new of itch in humans. These neurons also agents—histamine, protease activated treatments, and psychosocial aspects of responded to noxious mechanical and receptor-2 (PAR-2) agonist, and chloro- chronic itch. Highlights of the meeting thermal stimuli but did not respond to quine—in a manner that was reversed are presented below. histamine. A different subpopulation of by GRPR antagonists. The mutant mice STT neurons was unresponsive to cow- displayed normal nociceptive respons- Itch neurophysiology hage, but responded to histamine again es to noxious thermal and mechanical Since the discovery 10 years ago of over a time course matching that of itch stimuli or tissue inflammation. unmyelinated (C-fiber) afferents in sensation. Their data suggest the exis- Jeffrey Mogil (McGill University, humans that are selectively responsive tence of separate populations of STT Montreal, Canada) discussed the role to histamine but mechanically insensi- neurons that signal itch of different ori- of genetic factors in the variability of tive, it has been debated whether these gins to several thalamic nuclei involved histamine- and choloroquine-evoked fibers are the only ones that transmit in encoding itch. scratching among 11 different inbred itch. Clinically, it is well known that Gil Yosipovitch (Wake Forest mouse strains, which differed up to potent oral antihistamines do not relieve University, Winston-Salem, NC) pre- 2.5-fold. Furthermore, he demonstrated most types of itch. Moreover, mechani- sented data from a study using a new that female mice exhibited significantly

1Departments of Dermatology, Neurobiology, and Anatomy, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA; and 2Section of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, California, USA Correspondence: Dr Gil Yosipovitch, Department of Dermatology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA. E-mail: [email protected]

more pruritogen-evoked scratching (by mediated. He reported that the volt- with pruritus resistant to other treat- 23%) compared with male mice. He age-dependent calcium channel α2ð-1 ments. The results demonstrated signifi- also provided evidence for a negative subunit is involved in itch signaling cant reduction in itch intensity with a correlation between itch and pain, such by afferent nerve fibers of mice with rather safe profile. that mouse strains exhibiting greater allergic itch induced by an extract of Sonja Ständer (University of Münster, sensitivity to noxious stimuli exhibited mosquito salivary gland. Gabapentin Germany) presented results of a large, less scratching, and vice versa. These reduced scratching evoked by mos- open-label study of 72 patients with findings may lead to the future identifi- quito salivary gland extract, but not chronic itch of different origins. The cation of itch-related genes. histamine, in a dose-dependent man- selective serotonin reuptake inhibitors Makoto Tominaga (Okazaki Institute, ner. This calcium-channel subunit was paroxetine and fluvoxamine signifi- Tokyo, Japan) presented an overview extensively coexpressed with the cap- cantly reduced itch in more than 50% of the possible role of thermosensitive saicin and heat receptor TRPV1 in sen- of patients. transient receptor potential (TRP) chan- sory neurons. A poster from the same A major highlight of the workshop nels in itch. He also presented data group demonstrated that itch associ- was the Handwerker Prize, awarded demonstrating that skin keratinocytes ated with hypersensitization to mos- to a junior scientist whose poster was express a variety of thermoTRP chan- quito bites is mediated by a lipoxin A4 voted best by an impartial commit- nels and may be involved in detecting (LXA), a 5-lipoxygenase metabolite. tee. The prize is named in honor of temperature and pruritic stimuli along Furthermore, mice with hypersensitiv- Hermann Handwerker (University of with sensory nerve fibers. ity to mosquito bites had elevated CD4 Erlangen, Germany), a pioneer in the T cells with receptors to LXA. These field of itch research who has trained Neuromodulators and itch CD4 cells induced LXA4 itch in mice. many neuroscientists in the field. The Martin Steinhoff (University of Münster, award was given to Steve Davidson Germany) presented an overview of the Treatments for itch (University of Minnesota, Minneapolis), mediators of neurogenic inflammation Several new antipruritic treatment who showed that scratching reduced and the cross-talk among mast cells, modalities were presented at the meet- the histamine- and cowhage-evoked dendritic cells, and T cells involved in ing. One of the new concepts is that responses of primate STT neurons in a the itch response. Mediators such as an imbalance in central µ- and κ-opi- manner consistent with the ability of endothelin-converting enzyme 1 and oids may play a role in chronic itch. scratching to relieve itch. neutral endopeptidase control sub- Support for this concept was presented The 5th International Workshop for stance-P degradation and neurokinin- by Hiroshi Umeuchi (Toray Industries, the Study of Itch is scheduled to take A-mediated signaling of inflammation Urayasu, Japan) in a study of 59 patients place in Kyoto, Japan, 25–28 October and itch. An important role for proteases with primary biliary cirrhosis (PBC), a 2009, and will be organized by Kenji and their respective PAR receptors was cholestatic liver disease that is associ- Takamori of Juntendo University, initially reported by Steinhoff 7 years ated with severe itch. Patients experi- Urayasu, Japan. For more information ago and continues to be extensively encing itch exhibited higher plasma about future meetings, visit the IFSI investigated by his group. Interactions concentration of µ-opioids compared online at http://www.itchforum.org. with interleukin-31, a cytokine recently with patients not experiencing itch. CONFLICT OF INTEREST found to be a pruritogen in atopic ecze- In a mouse model of PBC, nalfurafine Dr. Yosipovitch served as a consultant and ma, were mentioned as potential targets hydrochloride, a κ-agonist, signifi- member of the advisory board of Acologix, which for future antipruritic medications. cantly inhibited scratching behavior. is developing a κ-agonist for the treatment of itch. Yashushi Kuraishi (Toyoma Kenji Takamori (Juntendo University, *The 4th International Workshop for the University, Japan) presented data that Urayasu, Japan) reported the results of Study of Itch was held at the Hilton San refuted the common notion that mos- a large double-blind study using nal- Francisco Financial District in San Francisco, quito-bite itch is solely histamine- furafine in 337 hemodialysis patients California, USA, 9–11 September 2007.