News & Events

NIAMS Itch Research Roundtable Summary

Summary Updated December 30, 2010

Friday, October 29, 2010

NIH Campus, Building 31, Room 6C10
Bethesda, Maryland

Co-chairs
Stephen I. Katz, M.D., Ph.D., NIAMS
Hung Tseng, Ph.D., NIAMS
Robert LaMotte, Ph.D., Yale University School of Medicine
Ethan Lerner, M.D., Ph.D., Massachusetts General Hospital

Introduction

The NIAMS organizes four to five roundtables on an annual basis as a part of the Institute’s long-range planning process. Over the long-term, these discussions help shape the Institute’s thinking about areas of importance in our basic, translational, and clinical research portfolios.

The purpose of the October 29, 2010, roundtable was to assess the state of itch research, in terms of defining its frontiers, evaluating its progress, and identifying needs and new opportunities. Specifically, recent progress in revealing itch neuronal pathways, using laboratory and animal models, and the implications of these findings in human beings were discussed. The overriding goal of the roundtable was to explore the translation of these models into human studies. This summary reflects the opinions of the participants and the colleagues they polled prior to the meeting.

Clinical Itch

Itch (also known as pruritus) is a common symptom of many skin diseases, and can be a comorbidity of disorders in other organ systems, such as hepatic diseases, uremia, HIV/AIDS, and some drug treatments. Chronic itch also occurs in certain psychological disorders, such as obsessive-compulsive disorder. Itch may have different manifestations across illnesses and patient populations, which can include distinct pain sensations, such as burning or stinging, and is reflected in the way that the sufferers scratch. The biological purpose of itch sensation remains debatable. By stimulating scratching behavior, for example, itch may serve to prevent deeper penetration of insects or microorganisms (e.g., hookworms or scabies mites) burrowing into human skin. However, the scratching reaction is usually too late to have any effect on the invading organism, but it may be pleasurable and provide some relief of the symptom. On the other hand, scratching behavior can be detrimental in situations, such as wound healing or inflammation (by reopening the wound or introducing a new infection). Hence, the evolutionary value of this sensation is not entirely clear.

Mechanisms of Itch Transmission and Components

The development of effective pharmacologic treatments for itch has been hampered by poor knowledge of its underlying mechanisms to target in therapeutics. Discoveries and approaches from the closely related and more mature field of pain research have already contributed significantly to the current understanding of itch. Investigations with mouse, rat, dog, and non-human primate models have identified many itch transmission pathways. Initial studies with human subjects and tissue samples, such as cultured patient biopsies, have corroborated some of the findings in animals. Imaging of human skin innervation, developed for neurobiology research and neurological clinical practice, is also bringing important insights.

After stimulation with a pruritogen, or itch-inducing agent, different sites of the body, and their particular molecular and cellular components, appear to have specific roles in the transmission of itch. In the periphery, keratinocytes—the primary cell type in the outer layer of skin, or epidermis—are believed to be the main, direct portal of pruritogens, through receptors, such as the transient receptor potential vanilloid type 3 (TRPV3) and itch-specific gastrin-responsive peptide receptors (GRPRs).

Other cells in the periphery seem to extend the itch sensory network beyond keratinocytes, such as certain immune cells that may be involved through more indirect mechanisms of itch transmission. For example, mast cells can release histamine, in response to a variety of ligands, which can trigger itch signals to the central nervous system (CNS). In addition, histamine can also stimulate T cells to release cytokines that can induce inflammatory activity, such as interleukin 31 (IL-31). Langerhans cells, immune cells found exclusively in skin, can also stimulate T cells. Many of these molecular and cellular mediators are disease-specific; for example, antihistamines are effective treatments for urticaria, but not for atopic dermatitis.

With evidence from animal studies, two primary models have emerged for the transmission of itch from the periphery to the CNS. In the labeled line model, there are distinct neurons that transmit itch or pain. In the selectivity theory, itch and pain are carried by the same type of neuron, but the two different sensations are determined by the specific anatomical location of the neuron termini in the periphery and the CNS, and the signals they receive. In addition, pain can inhibit itch, which may be the basis for itch occurring as an adverse side effect of some pain medications (e.g., morphine). Pruriceptors (itch receptors) on neurons include the G-protein coupled receptors (GPCRs), such as the histamine receptors, protease-activated receptor 2 (PAR2), the serotonin 5-HT2 receptor, and the chloroquine receptor, Mrgpr. TRPV1 and TRPV3 may also be involved with itch transmission. The distribution of these receptors on neurons may change with development or progression of disease, or with age.

Signals traveling from the periphery along itch-related C and A? nerve fibers (which can be used selectively by specific pruritogens) are received by dorsal root ganglion (DRG) neurons, which release gastrin-responsive peptide (GRP) and other neurotransmitters. These molecular factors trigger itch-transmitting TRPV1 and GRPRs in the CNS. Subsequently, the itch signal finally reaches the brain through spinothalamic tract neurons.

Animal and human studies have revealed that transmission of itch sensation can be modulated by the central and peripheral nervous systems. Normal itch can be abnormally amplified in the spinal cord. Spinal injection (e.g., lidocaine) can have effects on peripheral nociceptors (pain receptors), and elimination of CNS itch inhibition in a mouse model suggests anti-dromal (CNS to the periphery) transmission of itch sensation. Differences in the number of nerve fibers, according to gender, race, age, and parts of the body can affect itch transmission.

Central sensitization is an emerging model for chronic pain and chronic itch, in which there is a change from the acute condition due to physical changes in the CNS. A constant, low level of spinal/CNS activation, or a release of itch regulation in the CNS, creates a hypersensitive system that can transmit itch with little stimulation from the periphery, and may be the basis for compulsive itching in some patients. Animal models of central sensitization that also induce itch are one demonstration of the interaction of itch and pain mechanisms. In the same vein, treatments for widespread neuropathic pain, such as gabapentin (an anti-convulsant approved for fibromyalgia treatment) may also relieve itch. Aberrant neuronal signaling, leading to persistent itch, may derive from neuronal (peripheral and central) damage that has been observed in various chronic diseases.

In addition to stimulation from pruritogens, itch transmission can be induced by signal modifiers. Neurite outgrowth can stimulate neurons, which may be a source of itching during scar formation. Hence, nerve growth factor (NGF), which is produced by mast cells and, sometimes, by keratinocytes, could also be involved in itch signaling.

Genetic polymorphisms in receptors may be responsible for population-specific, as well as disease-specific, itch responses. Changes in gene expression of itch-associated receptors have been observed with stimulation in the periphery, as well as DRGs and the CNS. Neurotransmitters may also confer specificity. For example, different opioid receptors play distinct roles in transmitting itch and pain signals in non-human primates.

Opportunities for Translation into Human Studies and Therapeutic Development

The afore-mentioned molecular and cellular components are novel targets for itch therapeutic development, such as NGF, IL-31, PAR2, and GRPR. Some receptors respond to mechanical stimulation or temperature, so mechanical or electrical stimulation, or cooling are potential treatments. Elucidation of mechanisms of itch transmission will inform the development of efficient evaluation tests and measures of neuronal mediators in the periphery and CNS, which can be applied to screening of potential therapeutic agents. Some of these screening assays may be amenable to high throughput technologies, such as those available through the trans-NIH Molecular Libraries and Imaging Initiative.

Advances and experiences from pain research have already contributed greatly to understanding itch. Future research efforts can glean information from the new and emerging pain therapies, such as GRPR antagonists that are currently under development. Some companies are testing some of their pain medications in itch.

Mouse models are very informative, and easily manipulated with genetic engineering. However, there are many concerns about the relevance of itch research findings from mouse models to humans:

  • Itch- and pain-specific neurons and receptors identified in mouse models may not have the same distinct functions in humans.
  • Structural differences in mouse and human epidermis may create differences in itch transduction, and downstream cellular activity (e.g., protease production).
  • Overexpression of many cytokines in mice will induce non-specific itch, whereas the itch mechanisms in humans appear to be more complex.
  • Current mouse models correspond to acute itch, whereas clinical itch tends to be chronic.
  • Linking itch mechanisms from animal models to the spectrum of itch descriptions in human patient populations can be challenging, because some behaviors in animal models, such as scratching, licking, and biting that are attributed to the condition may be unrelated to it.

Many successful pain interventions in mice have not worked in human clinical trials. Hence, mouse models in itch can serve as one piece of information to approach treatment of the condition in humans. Improvements in correlating animal models with clinical itch could include creation of a chronic itch condition by ablating inhibitory pain neurons, through molecular or genetic manipulation. Back-crossing of mouse strains for skin diseases and itch-specific neuronal pathways may yield more effective models of specific itch phenotypes relevant to human disease, and automation and other improvements could aid the quantification of itch-related behaviors. Further development and testing of dog and non-human primate itch models may also enhance the efficiency of translating interventions into human testing. In particular, non-human primates may naturally display (and can also be trained) behaviors that are more relevant to human itch.

Cultured patient biopsies and models for skin differentiation can indicate changes in gene expression, and downstream molecular and cellular mediators, in response to pruritogens and successful interventions from animal studies. Nerve cells differentiated from human stem cells may be useful research tools if they express itch-specific receptors. Imaging techniques, such as skin innervation and confocal microscopy of patient tissue samples, can be enhanced with itch-specific markers.

Multidisciplinary collaborations involving experts in neurobiology, skin biology, immunology, and dermatology will be critical to moving new discoveries in the laboratory into human studies. These new research groups can design the next phase of basic and translational research to correspond with clinical characteristics of itch in specific diseases. To inform these efforts, various itch subphenotypes can be characterized with more epidemiological studies, as well as brain imaging, and molecular and cellular analysis of skin biopsies. In addition, continued research in the psychosocial and behavioral aspects of itch and itch comorbidities, and incorporation of patient-reported outcomes in itch research, could expand understanding of the condition, and may also identify important bedside-to-bench research opportunities.

Meeting Participants

BAKER, Carl C., M.D., Ph.D.
Director, Keratinocyte Biology and Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS

BLOCK, Julie
President and CEO
National Eczema Association

CARSTENS, Earl, Ph.D.
Professor, Department of Neurobiology, Physiology and Behavior
University of California, Davis

CARTER, Robert, M.D.
Deputy Director
NIAMS

CHEN, Zhou-Feng, Ph.D.
Professor, Departments of Anesthesiology, Psychiatry, and Developmental Biology
Washington University in St. Louis

CIBOTTI, Ricardo, Ph.D.
Director, Immunobiology and Immune Diseases of Skin Program
Division of Skin and Rheumatic Diseases
NIAMS

DONG, Xinzhong, Ph.D.
Assistant Professor, Department of Neuroscience
Johns Hopkins University School of Medicine

KATZ, Stephen I., M.D., Ph.D.
Director
NIAMS

KO, Mei-Chuan (Holden), Ph.D.
Research Associate Professor, Department of Pharmacology
University of Michigan Medical School

LaMOTTE, Robert H., Ph.D.
Professor
Departments of Anesthesiology and Neurobiology
Yale University School of Medicine

LERNER, Ethan, M.D., Ph.D.
Associate Professor, Cutaneous Biology Research Center
Massachusetts General Hospital

MOEN, Laura, Ph.D.
Director, Division of Extramural Research Activities
NIAMS

OAKLANDER, Anne Louise, M.D.
Associate Professor, Department of Neurology
Massachusetts General Hospital

ROSS, Sarah, Ph.D.
Postdoctoral Fellow, Department of Neurobiology
Harvard Medical School

SERRATE-SZTEIN, Susana, M.D.
Director, Division of Skin and Rheumatic Diseases
NIAMS

STEINHOFF, Martin, M.D., Ph.D.
Professor, Department of Dermatology
University of California, San Francisco School of Medicine

TSENG, Hung, Ph.D.
Director, Extracellular Matrix Biology and Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS

WOLPOWITZ, Deon, M.D., Ph.D.
Assistant Professor, Department of Dermatology
Boston University

WOOLF, Clifford, M.D., Ph.D.
Professor, F.M. Kirby Neurobiology Center
Children’s Hospital Boston

YOSIPOVITCH, Gil, M.D.
Professor, Department of Dermatology
Wake Forest University School of Medicine