Itch

Itch Basic Mechanisms and Therapy

edited by Gil Yosipovitch Wake Forest University School of Medicine Winston-Salem, North Carolina, U.S.A.

Malcolm W. Greaves University of London London, England and Singapore General Hospital Singapore, Republic of Singapore

Alan 6. Fleischer, Jr. Wake Forest University School of Medicine Winston-Salem, North Carolina, U.S.A.

Francis McGlone Unilever Research and Development Wirral, England and University of Wales Bangor, Wales

M A R C E L

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PRINTED IN THE UNITED STATES OF AMERICA

BASIC AND CLINICAL DERMATOLOGY

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Series Editors

ALAN R. SHALITA, M.D. Distinguished Teaching Professor and Chairman

Department of Dermatology State University of New York

Health Science Center at Brooklyn Brooklyn, New York

DAVID A. NORRIS, M.D. Director of Research

Professor of Dermatology The University of Colorado Health Sciences Center

Denver, Colorado

Cutaneous Investigation in Health and Disease: Noninvasive Methods and Instrumentation, edited by Jean-Luc Leveque Irritant Contact Dermatitis, edited by Edward M. Jackson and Ronald Goldner Fundamentals of Dermatology: A Study Guide, Franklin S. Glickman and Alan R. Shalita Aging Skin: Properties and Functional Changes, edited by Jean-Luc Leveque and Pierre G. Agache Retinoids: Progress in Research and Clinical Applications, edited by Maria A. Livrea and Lester Packer Clinical Photomedicine, edited by Henry W. Lim and Nicholas A. Soter Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice and Development, edited by John W. Rippon and Robert A. Fromtling Oxidative Stress in Dermatology, edited by Jurgen Fuchs and Lester Packer Connective Tissue Diseases of the Skin, edited by Charles M. Lapiere and Thomas Krieg Epidermal Growth Factors and Cytokines, edited by Thomas A. Luger and Thomas Schwarz Skin Changes and Diseases in Pregnancy, edited by Marwali Harahap and Robert C. Wallach Fungal Disease: Biology, Immunology, and Diagnosis, edited by Paul H. Jacobs and Lexie Nall lmmunomodulatory and Cytotoxic Agents in Dermatology, edited by Charles J. McDonald

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Cutaneous Infection and Therapy, edited by Raza Aly, Kart R. Beutner, and Howard 1. Maibach Tissue Augmentation in Clinical Practice: Procedures and Techniques, edited by Arnold William Klein Psoriasis: Third Edition, Revised and Expanded, edited by Henry H. Roenigk, Jr., and Howard 1. Maibach Surgical Techniques for Cutaneous Scar Revision, edited by Mamali Harahap Drug Therapy in Dermatology, edited by Lany E. Millikan Scarless Wound Healing, edited by Hari G. Garg and Michael T. Long- aker Cosmetic Surgery: An Interdisciplinary Approach, edited by Rhoda S. Narins Topical Absorption of Dermatological Products, edited by Robert L. Bronaugh and Howard 1. Maibach Glycolic Acid Peels, edited by Ronald Moy, Debra Luffman, and Lenore S. Kakita Innovative Techniques in Skin Surgery, edited by Marwali Harahap Safe Liposuction, edited by Rhoda S. Narins Psychocutaneous Medicine, edited by John Y. M. Koo and Chai Sue Lee Skin, Hair, and Nails: Structure and Function, edited by Bo Forslind and Magnus Lindberg Itch: Basic Mechanisms and Therapy, edited by Gil Yosipovitch, Malcolm W. Greaves, Alan 8. Fleischer, Jr., and Francis McGlone

ADDITIONAL VOLUMES IN PREPARA TION

Vitiligo: Problems and Solutions, edited by Torello Loffi and Jana Hercogova

Photoaging, edited by Darrel S. Rigel, Robert A. Weiss, Henry W. Lim, and Jeffrey S. Dover

To my wife, Galit, my children, Dan and Natalie,and my devoted parents, Shifra and Zvi.

Without their continuous support, love, and understanding,this book would not have been possible.

G. Y.

To all my itchy patients who taught me that there is moreto pruritus than scratching the surface.

M. W. G.

To my wonderful and patient wife, Anne.

A. B. F.

For all those who suer still, in the hope that our growing knowledgeof the mechanisms will enhance our therapies.

F. M.

Series Introduction

Over the past decade, there has been a vast explosion in new informationrelating to the art and science of dermatology as well as fundamental cuta-neous biology. Furthermore, this information is no longer of interest only tothe small but growing specialty of dermatology. Scientists from a wide varietyof disciplines have come to recognize both the importance of skin in fun-damental biological processes and the broad implications of understandingthe pathogenesis of skin disease. As a result, there is now a multidisciplinaryand worldwide interest in the progress of dermatology.

With these factors in mind, we have undertaken to develop this series ofbooks specically oriented to dermatology. The scope of the series is pur-posely broad, with books ranging from pure basic science to practical, appliedclinical dermatology. Thus, while there is something for everyone, all volumesin the series will ultimately prove to be valuable additions to the dermatolo-gists library.

The latest addition to the series, edited by Gil Yosipovitch, MalcolmGreaves, Alan Fleischer, and Francis McGlone, is both timely and pertinent.The authors are well-known authorities in the eld. We trust that this volumewill be of broad interest to scientists and clinicians alike.

Alan R. ShalitaSUNY Health Science Center

Brooklyn, New York

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Foreword

You know that I would cut oMy hands to help you

But if I did I wouldnt haveAnything to scratch with

And then Id be ofNo use at all.

Don McGonigal, The Itch, 1991

Itch is one of the most distressing sensations that substantially impair thequality of life, and in some cases it may even cause psychological disorders.It is a symptom of many skin diseases and may be caused by a variety of sys-temic diseases.

The enormous developments in biotechnology of the past ve yearshave enabled major progress in neurophysiological research, allowing us to

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dene novel pathways for itch. Improved understanding of the pathophysi-ology and molecular basis of itching ultimately has stimulated the search forand development of novel therapeutic strategies. In the current book Drs.Yosipovitch, Greaves, Fleischer, and McGlone were able to motivate out-standing scientists and clinicians to provide, in a multidisciplinary approach,the most current knowledge of the complex experimental, clinical, andtherapeutic aspects of itching. This includes recent research concerning basicmechanisms of itching such as central nervous aspects, animal and humanmodels, and neuropeptides as well as their respective receptors. Furthermore,emphasis is put on new techniques of itch evaluation such asmicrodialysis andquestionnaires. Another important topic is the symptom of itch in dermato-logical as well as systemic diseases. Finally, as a result of our improvedunderstanding of the pathophysiology of itching, several chapters address themost up-to-date therapeutic developments, including new drugs and psycho-logical approaches.

In summary, the important insights provided by the expertise of theseoutstanding contributors will be of major interest to clinicians managing thischallenging symptom as well as to researchers interested in the pathogenesisof itching.

Thomas A. Luger, M.D.Professor and Chairman

Department of DermatologyUniversity Clinics Munster

Munster, Germany

Forewordviii

Preface

For many years progress in understanding the neuropathophysiology andmolecular basis of itch has been handicapped by a lack of specic andsensitive investigational methodologies for human subjects and the unsuit-ability of animal models. Researchers have nally begun to overcome thesediculties, with important clinical implications. Recent neurophysiologicalresearch has made possible a more accurate description of neural pathwaysof itch and has conrmed the distinctiveness of itch pathways in comparisonwith pain pathways.

We were motivated to work on this book by consideration of patientsaicted by chronic and intractable itch and our desire to contribute to abetter understanding of this common, bothersome symptom. The idea wasproposed in October 2001 at the International Workshop for the Study ofItch in Singapore. This was the rst multidisciplinary meeting that broughtclinicians and scientists together to address problems related to itch.

This book presents a concise discussion of the basic aspects of itch,various diseases in which itch constitutes a major problem, and methodsemployed in its diagnosis and management. It is designed to be a source of

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information for both dermatologists and nondermatologists who treat itch,as well as for researchers in the eld of neurophysiology and pharmacology.The organization of the chapters reects our views as to how the reader canbest utilize these materials. The book has six parts. Part I contains a pro-posed clinical classication of itch, based on an improved understanding ofits neurophysiology. Part II reviews the basic mechanisms of itch. Part IIIaddresses the evaluation of the patient with itch. Part IV focuses on epi-demiology and characteristics of itch in skin and systemic diseases. Part Vprovides an overview of the dierent methods for the treatment of itch cur-rently in use or in clinical trials. The last part consists of three chapters ad-dressing the social and psychological aspects of itch.

The authors were selected for their expertise and interest in this eld.While eorts were made to avoid repetition, each author was free to presenthis or her own concepts and thoughts. The progress documented in thisbook is encouraging and is a direct result of expanded interest in the prob-lem of itch in both the scientic and clinical communities.

Gil YosipovitchMalcolm W. GreavesAlan B. Fleischer, Jr.

Francis McGlone

Prefacex

Contents

Foreword Thomas A. Luger viiPreface ixContributors xv

Part I. Clinical Classication of Itch

1. Denitions of Itch 1Gil Yosipovitch and Malcolm W. Greaves

Part II. Basic Mechanisms of Itch

2. Neurophysiologic Basis of Itch 5Martin Schmelz and Hermann O. Handwerker

3. Pain and Itch 13Martin Schmelz and Hermann O. Handwerker

4. Central Neural Mechanisms of Itch 21David Andrew and A. D. Craig

5. Animal Models of Itch: Scratching Away at the Problem 35Earl Carstens and Yasushi Kuraishi

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6. Histamine-Induced Discriminative and AectiveResponses Revealed by Functional MRI 51Francis McGlone, Roman Rukwied, Matt Howard,and David Hitchcock

7. Central Nervous System Imaging of Itch with PET 63Ulf Darsow, Alexander Drzezga, and Johannes Ring

8. Skin Nerve Anatomy: Neuropeptide Distribution and ItsRelationship to Itch 71Dieter Metze

9. Substance P and Itch 87Tsugunobu Andoh and Yasushi Kuraishi

10. Peripheral Opiate Receptor System in Human Epidermisand Itch 97Paul Lorenz Bigliardi and Mei Bigliardi-Qi

11. Antipruritic Activity of a Novel K-Opioid ReceptorAgonist, TRK-820 107Jun Utsumi, Yuko Togashi, Hideo Umeuchi, Kiyoshi Okano,Toshiaki Tanaka, and Hiroshi Nagase

12. Putative Role of Cannabinoids in Experimentally InducedItch and Inammation in Human Skin 115Roman Rukwied, Melita Dvorak, Allan Watkinson,and Francis McGlone

13. Itch Models in Animals, with Special Emphasis on theSerotonin Model in Rats 131Jens Schiersing Thomsen

14. Human Itch Models, with Special Emphasis on Itch inSLS-Inamed and Normal Skin 139Jens Schiersing Thomsen

Part III. Evaluation of Patients with Itch

15. Microdialysis in Itch Research 147Martin Schmelz

Contentsxii

16. Measuring Nocturnal Scratching in Atopic Dermatitits 161Toshiya Ebata

17. Itch Questionnaires as Tools for Itch Evaluation 169Gil Yosipovitch

Part IV. Epidemiology and Characteristics of Itch

18. Epidemiology of Itching in Skin and Systemic Diseases 183Gil Yosipovitch

19. Uremic Pruritus: New Perspectives and Insights fromRecent Trials 193Thomas Mettang, Dominik Mark Alscher,and Christiane Pauli-Magnus

20. Pruritus Complicating Liver Disease 205Nora V. Bergasa and E. Anthony Jones

21. Itch in HIV-Infected Patients 219Maria I. Duque, Gil Yosipovitch, and P. Samuel Pegram

22. Neuropathic Pruritus 231Gil Yosipovitch, Rashel Goodkin, Ellen Mary Wingard,and Jerey D. Bernhard

23. Clinical Features of Itch in Atopic Eczema 241Ulf Darsow and Johannes Ring

24. Postburn Itch 247Robert D. Nelson

25. Pruritus in Lichen Simplex Chronicus and LichenAmyloidosis 255Yung-Hian Leow and Gil Yosipovitch

Part V. Treatment of Itch

26. Treatment of Pruritus in Internal and DermatologicalDiseases with Opioid Receptor Antagonists 259Sonja Stander and Dieter Metze

Contents xiii

27. Prospects for a Novel K-Opioid Receptor Agonist,TRK-820, in Uremic Pruritus 279Hiroo Kumagai, Shigeaki Matsukawa, Jun Utsumi,and Takao Saruta

28. Treatment of Pruritic Skin Diseases with TopicalCapsaicin 287Sonja Stander and Dieter Metze

29. Mechanistic and Clinical Assessment of ZangradoRRR, anExtract of the Amazonian Ethnomedicine Sangre deGrado, for the Treatment of Itch 305Mark J. S. Miller, Brian K. Reuter, John L. Wallace,Keith A. Sharkey, and Paul Bobrowski

30. Reduction in Itch Severity with TopicalImmunomodulators: A New Approach for Patients withInammatory Disease 315Alan B. Fleischer, Jr.

31. 5-HT3 Receptor Antagonists as Antipruritics 325Elke Weisshaar

32. Cutaneous Nerve Stimulation in Treatment of LocalizedItch 335Joanna Wallengren

Part VI. Social and Psychological Aspects

33. Psychosomatic Aspects of Pruritus 343Uwe Gieler, Volker Niemeier, Burkhard Brosig, and JorgKupfer

34. On Psychological Factors Aecting Reports of ItchPerception 351Elia E. Psouni

35. Itching as a Focus of Mental Disturbance 369Yuval Melamed and Gil Yosipovitch

Index 377

Contentsxiv

Contributors

Dominik Mark Alscher, M.D. Vice Medical Director, Department of Gen-eral Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart,Germany

Tsugunobu Andoh, Ph.D. Department of Applied Pharmacology, ToyamaMedical and Pharmaceutical University, Toyama, Japan

David Andrew, B.D.S., Ph.D. Research Fellow, Department of Neuro-science and Biomedical Systems, University of Glasgow, Glasgow, Scotland

Nora V. Bergasa,M.D. Associate Professor, Division ofDigestive and LiverDiseases, Department of Medicine, College of Physicians and Surgeons,Columbia University, New York, New York, U.S.A.

Jerey D. Bernhard, M.D. Professor, Department of Dermatology, Uni-versity of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.

Paul Lorenz Bigliardi, M.D. Department of Dermatology and Research,Basel University Hospital, Basel, Switzerland

Mei Bigliardi-Qi, Ph.D. Head, Department of Research and Dermatology,Basel University Hospital, Basel, Switzerland

Paul Bobrowski, B.S. Rainforest Pharmaceuticals, LLC, Scottsdale, Ari-zona, U.S.A.

xv

Burkhard Brosig, M.D., Ph.D. Clinic for Psychosomatics and Psychother-apy, Clinic for Psychosomatic Medicine, University Hospital of Giessen,Giessen, Germany

Earl Carstens, Ph.D. Professor, Section of Neurobiology, Physiology, andBehavior, University of California, Davis, Davis, California, U.S.A.

A. D. Craig, Ph.D. Atkinson Pain Research Scientist, Department ofNeurosurgery, Barrow Neurological Institute, Phoenix, Arizona, U.S.A.

Ulf Darsow, M.D. Department of Dermatology and Allergy Biederstein,Technical University of Munich, Munich, Germany

Alexander Drzezga, M.D. Senior Nuclear Medicine Physician, Departmentof Nuclear Medicine, Technical University of Munich, Munich, Germany

Maria I. Duque, M.D. Department of Dermatology, Wake Forest Univer-sity School of Medicine, Winston-Salem, North Carolina, U.S.A.

Melita Dvorak, Ph.D. School of Biological Sciences, University of Man-chester, Manchester, England

Toshiya Ebata, M.D. Assistant Professor, Department of Dermatology,Jikei University School of Medicine, Tokyo, Japan

Alan B. Fleischer, Jr., M.D. Professor and Chair, Department of Dermatol-ogy, Wake Forest University School of Medicine, Winston-Salem, NorthCarolina, U.S.A.

Uwe Gieler, M.D. Department of Psychosomatic Dermatology, Clinic forPsychosomatics and Psychotherapy, Justus-Liebig University, Giessen, Ger-many

Rashel Goodkin, M.D. Department of Dermatology, Lahey Clinic, Burling-ton, Massachusetts, U.S.A.

Malcolm W. Greaves, M.D., Ph.D., F.R.C.P. Professor Emeritus, Depart-ment of Dermatology, University of London, London, England, and Singa-pore General Hospital, Singapore, Republic of Singapore

Contributorsxvi

HermannO.Handwerker,M.D., Ph.D. Professor and Chair, Department ofPhysiology and Experimental Pathophysiology, University of Erlangen,Erlangen, Germany

David Hitchcock, Ph.D. Unilever Research and Development, Wirral,England

Matt Howard, Ph.D. University of Liverpool, Liverpool, England

E. Anthony Jones, M.D., D.Sc., F.R.C.P. Department of Gastrointestinaland Liver Diseases, AcademicMedical Center, Amsterdam, The Netherlands

Hiroo Kumagai, M.D. Assistant Professor, Department of Internal Medi-cine, Keio University School of Medicine, Tokyo, Japan

Jorg Kupfer, Ph.D. Department of Medical Psychology, Justus-Liebig Uni-versity, Giessen, Germany

Yasushi Kuraishi, Ph.D. Professor, Department of Applied Pharmacology,Faculty of Pharmaceutical Sciences, Toyama Medical and PharmaceuticalUniversity, Toyama, Japan

Yung-Hian Leow, M.D., M.Med., F.A.M.S. Senior Consultant Dermatol-ogist, National Skin Centre, Singapore, Republic of Singapore

Shigeaki Matsukawa, M.D. Director, Department of Internal Medicine,Inagi Municipal Hospital, Tokyo, Japan

FrancisMcGlone, Ph.D. Head and Professor, Cognitive Neuroscience, Uni-lever Research andDevelopment,Wirral, England, andAssociateDirector ofthe Center for Cognitive Neuroscience, University of Wales, Bangor, Wales

Yuval Melamed, M.D. Deputy Director and Lecturer in Psychiatry, TelAviv Faculty of Medicine, Lev-Hasharon Mental Health Center, Natania,Israel

Thomas Mettang, M.D., P.D. Vice Medical Director, Department of Gen-eral Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart,Germany

Dieter Metze, M.D. Professor, Department of Dermatology, University ofMunster, Munster, Germany

Contributors xvii

Mark J. S. Miller, Ph.D. Professor, Center for Cardiovascular Sciences,Albany Medical College, Albany, New York, U.S.A.

Hiroshi Nagase, D.Sc. Director, Pharmaceutical Research Laboratories,Toray Industries, Inc., Kamakura, Kanagawa, Japan

Robert D. Nelson, Ph.D. Director, Surgery Research Laboratory, Depart-ment of Surgery, Regions Hospital, St. Paul, Minnesota, U.S.A.

Volker Niemeier, M.D. Department of Psychosomatic Dermatology, Clinicfor Psychosomatics and Psychotherapy, Justus-Liebig University, Giessen,Germany

Kiyoshi Okano, Ph.D. Head, First Laboratory of Drug Development,Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura,Kanagawa, Japan

Christiane Pauli-Magnus, M.D. Department of Clinical Pharmacology andToxicology, University Hospital Zurich, Zurich, Switzerland

P. Samuel Pegram, M.D. Professor, Department of Infectious Diseases,Wake Forest University School of Medicine, Winston-Salem, North Car-olina, U.S.A.

Elia E. Psouni, B.Sc., M.Sc., Ph.D. Division of Neurophysiology, Depart-ment of Physiological Sciences, Lund University, Lund, Sweden

Brian K. Reuter, Ph.D. Postdoctoral Fellow, Center for CardiovascularSciences, Albany Medical College, Albany, New York, U.S.A.

Johannes Ring, Prof.Dr.med., Dr.phil. Professor and Director, Departmentof Dermatology and Allergy Biederstein, Technical University of Munich,Munich, Germany

Roman Rukwied, Ph.D. Unilever Research and Development, Wirral, Eng-land

Takao Saruta, M.D. Professor, Department of InternalMedicine, Nephrol-ogy and Hypertension, Keio University School of Medicine, Tokyo, Japan

Martin Schmelz, M.D., Ph.D. Department of Anesthesiology Mannheim,University of Heidelberg, Mannheim, Germany

Contributorsxviii

Keith A. Sharkey, Ph.D. Professor, Neurosciences Research Group, Uni-versity of Calgary, Calgary, Alberta, Canada

Sonja Stander, M.D. Department of Dermatology, University of Munster,Munster, Germany

Toshiaki Tanaka, Ph.D. Head, Drug Discovery Laboratory, Pharmaceut-ical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa,Japan

Jens Schiersing Thomsen, M.D., Ph.D. Department of Dermatology, Gen-tofte University Hospital, Copenhagen, Denmark

Yuko Togashi, M.Sc. Pharmaceutical Research Laboratories, Toray Indus-tries, Inc., Kamakura, Kanagawa, Japan

Hideo Umeuchi, M.S. First Laboratory of Drug Development, Pharma-ceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kana-gawa, Japan

Jun Utsumi, V.M.D., D.Sc. General Manager, Corporate Research Plan-ning Department, Toray Industries, Inc., Tokyo, Japan

John L. Wallace, Ph.D. Professor, Departments of Pharmacology andMedicine, University of Calgary, Calgary, Alberta, Canada

Joanna Wallengren, M.D., Ph.D. Associate Professor, Department of Der-matology, University Hospital, Lund, Sweden

Allan Watkinson, Ph.D. Unilever Research and Development, Wirral,England

Elke Weisshaar, M.D. Consultant, Occupational and Environmental Der-matology, Department of Social Medicine, University of Heidelberg, Heidel-berg, Germany

Ellen Mary Wingard, M.D. Department of Dermatology, University ofMassachusetts Medical School, Worcester, Massachusetts, U.S.A.

Gil Yosipovitch, M.D. Associate Professor of Dermatology and Neuro-science,Department ofDermatology, andNeuroscience Center,Wake ForestUniversity School of Medicine, Winston-Salem, North Carolina, U.S.A.

Contributors xix

1Definitions of Itch

Gil Yosipovitch

Wake Forest University School of Medicine, Winston-Salem,North Carolina, U.S.A.

Malcolm W. Greaves

University of London, London, England, and Singapore General Hospital,Singapore, Republic of Singapore

The simple denition of itch rst proposed by Samuel Hafenreer (1) 340years ago as an unpleasant sensation provoking the desire to scratch isstill widely used; however, as indicated by Savin (2), it is unsatisfactorybecause unpleasant is a subjective adjective and is not a descriptor capableof precise denition. We also wish to point out that many subjects rub butdo not scratch in response to itch. The well-known sign of polished nger-nails bears witness to this fact, as does the familiar observation that patientswith urticaria, a severely pruritic disorder, almost never have scratch marks.

Although a satisfactory denition of itch remains elusive, at least tous, it is worth attempting operational denitions of dierent types of itch forthe assistance of those working in this dicult eld.

As with any other subjective symptom, denitions pose problems. Theyserve as an operational framework and we do not intend to constrain updatesin the future. The terms and denitions are not meant to be a comprehensiveglossary but rather a standard glossary for people who work in the eld ofitch.

1

Acute itch. An unpleasant sensation which provokes the desire toscratch for a limited period of time ranging from seconds to a week. It iselicited by substantial inammation or injury of body tissue and activationof pruritoceptive bers at the site of local tissue damage. This alters the re-sponse of pruritoceptives, their central connections, and the autonomic ner-vous system in the region. The report of itch can stop long before healinghas completed. The patient can still have erythema and eczema even thoughthe itch has subsided. This type of itch is seen after insect bites, acutedermatitis, and some skin diseases.

Itch that persists for weeks, months, or years is not classied underthis category.

Chronic itch. Chronic itch diers from acute itch because therapiesthat provide transient itch relief do not resolve the underlying pathologicalprocess. Chronic itch will continue when treatment stops. Chronic itch cor-rodes the spirit and the quality of life. It may totally destroy a patientssocial life and even lead to suicide as in patients with chronic pain.

Because chronic itch is unrelenting, aective and environmental stressfactors, such as heat and dryness, may exacerbate the intensity and per-sistence of itch. Medical treatment would be helpful to prevent or reduce theitch and to shorten the duration of inammation and thereby shorten itch.

Intractable itch. This itch cannot be treated in the generally acceptedcourse of medical practice. A more detailed denition for intractable itch isa chronic itch state in which the cause cannot be removed or otherwisetreated, and in the generally accepted course of medical practice no relief orcure of the cause of itch is possible or none has been found after reasonableeorts. This denition communicates a message of hopelessness, especiallywhen we state that chronic itch is treatable. It is important to acknowledgethat such patients are encountered weekly in dermatology clinics, and theydo suer. In these cases, a more holistic approach is required by an inter-disciplinary team, with the involvement of both patients and their families.It integrates pharmacologic and nonpharmacologic treatment with neededpsychotherapy and rehabilitation.

Alloknesis. This type of itch is due to an innocuous stimulus whichdoes not normally provoke itch (3). This term is derived from the termallodynia, which is pain due to a stimulus which does not normally invokepain. It is important to recognize that alloknesis involves a change in thequality of a sensation, whether tactile, mechanical, or of any other sort. Theoriginal modality is normally nonitchy, but the response is itchy. It has beendescribed in atopic eczema after slight mechanical stimulation with woolbers in a noninvolved area surrounding an itching lesion. Another common

Yosipovitch and Greaves2

clinical example in patients with atopic eczema is sweat, which prompts in-tense itching, especially in front of the neck and exural areas.

Alloknesis has also been demonstrated in experimental itch models inhumans by intracutaneous and subcutaneous injections of histamine (3,4). Most probably, it can be demonstrated in other itchy dermatosis andin neuropathic itch, but there are as yet no reported instances of suchdemonstrations.

I. CLASSIFICATION OF DIFFERENT TYPES OF ITCH

Recently, a denition of dierent types of itch was provided (5,6). This mayhelp us to evaluate and treat itch in a more meaningful way both for theindividual patient and for the comparison of potential therapies in studies.

Pruritoceptive itch. Itch originating in the skin due to inammation,dryness, or other skin damage. Examples include itch due to xerosis, urti-caria, insect bite reactions, and scabies, to name a few.

Neuropathic itch. Itch due to pathology located at any point alongthe aerent pathway. Examples include postherpetic neuralgic itch, brach-ioradial itch, itch associated with cerebral vascular events in the CNS, itchassociated with multiple sclerosis and brain tumors (see Chapter 22).

Neurogenic itch. Itch that originates centrally but without evidenceof neural pathology, exemplied by itch of cholestasis due to the action ofopioid neuropeptides on opioid receptors (see Chapter 10).

Psychogenic itch. Itch associated with psychological abnormalities,e.g., itch in a delusional state of parasitophobia or itch in a compulsivedisorder (7).

Of course, there is no reason why one type of itch may not coexistconcurrently with another in a given patient, e.g., itch in a patient withprurigo nodularis, where there could be both a pruritoceptive itch as well asa neurogenic itch involved.

REFERENCES

1. Hafenreer S. Nosodochium, in quo cutis, eique adaerentium partium, aectusomnes, singulari methodo, et cognoscendi e curandi delisime traduntur. Ulm:Kuhnen, 1660:98102.

2. Savin J. How should we dene itching? J Am Acad Dermatol 1998; 39:268269.3. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation

Definitions of Itch 3

and itchy skin (alloknesis) produced by intracutaneous injection of histamine.Somatosens Mot Res 1991; 8:271279.

4. Heyer G, Groene D, Martus P. Ecacy of naltrexone on acetylcholine-induced

alloknesis in atopic eczema. Exp Dermatol 2002; 11:448455.5. Twycross R, Greaves MW, Handwerker H, et al. Itch: scratching more than the

surface. Q J Med 2003; 96:726.

6. Yosipovitch G, Greaves M, Schmelz M. Itch. Lancet 2003; 361:690694.7. Bernhard JD. Neurogenic pruritus and strange sensations. In: Bernhrad JD, ed.

Itch Mechanisms and Management of Pruritus. New York: McGraw Hill,

1994:185202.

Yosipovitch and Greaves4

2Neurophysiologic Basis of Itch

Martin Schmelz

University of Heidelberg, Mannheim, Germany

Hermann O. Handwerker

University of Erlangen, Erlangen, Germany

I. ITCH PATHWAYS

Low-level activation in nociceptors has been proposed to initiate the itchsensation, whereas upon higher discharge frequency, the sensation switches topain (intensity theory). In line with this theory, the application of high concen-trations of pruritics, e.g., histamine, may be painful. However, low concen-trations of algogens do not generally cause itch, but less intense pain. Themost convincing argument against the intensity theory was generated usingintraneural microstimulation in aerent nerves in humans: electrical stimu-lation via a microelectrode implanted in an aerent nerve of volunteersinduced either the threshold sensation of pain or, more rarely, the sensationof itch. Increasing the stimulation frequency increased the magnitude of painor of itch. No switch of the sensation from itch to pain was observed.Likewise, the decrease of stimulation frequency at a painful site decreasedthe magnitude of pain, but did not induce the sensation of itch (1). Accordingto these results, ring frequency in nociceptors cannot account for thedierentiation between pain and itch. Thus, it has to be assumed that pruriticspreferentially excite a certain subgroup of nociceptors which give rise to theitch sensation. However, the most common type of C-bers, the mechanoheat

5

nociceptors (CMH or polymodal nociceptors), which have been exten-sively investigated in animal (2) and human (3) skin, are either insensitive tohistamine or only very weakly activated. Thus, they cannot account for thelasting itch sensation observed, for example, following histamine applicationin the skin. Recently, C-nociceptors have been discovered among mechano-insensitive C-nociceptors (4), which respond to histamine iontophoresis inparallel to the itch ratings of the subjects (Fig. 1) as postulated before (5).Characteristics of itch bers comprise low conduction velocity, largeinnervation territories, mechanical unresponsiveness, and high transcutane-ous electrical thresholds. It is interesting to note that corresponding to thelarge innervation territories of these bers, two-point discrimination forhistamine-induced itch is poor (15 cm in the upper arm) (6). In the group ofunmyelinated nociceptors, about 80% respond to mechanical, heat, and

Figure 1 The upper panel shows instantaneous discharge frequency of a mechano-and heat-insensitive C-ber (CMiHi) in the supercial peroneal nerve followinghistamine iontophoresis (marked as open circles in the diagram). The unit was not

spontaneously active before histamine application, but continued to re for about 15min further (not shown in the diagram).The lower panel shows average itchmagnituderatings of a group of 21 healthy volunteers after an identical histamine stimulus.Ratings at 10 s intervals on a visual analog scale (VAS) with the end points no itch

and unbearable itch. Bars: standard error of means. (From Ref. 4.)

Schmelz and Handwerker6

chemical stimuli. They have been termed polymodal nociceptors (7). Theremaining 20% do not respond to mechanical stimulation. These bers havebeen classied as silent or sleeping nociceptors (811). They can bereadily activated by chemical stimuli (12) and can also be sensitized tomechanical stimulation under inammatory conditions (12,13). Units witha strong and lasting histamine response are found only in the group ofmechano-insensitive nociceptors. They comprise about 20% of the mechano-insensitive class of nociceptors (Fig. 2).

II. CHEMICAL RESPONSIVENESS OF ITCH FIBERS

There are only a few mediators which can induce histamine-independentpruritus. Prostaglandins were found to enhance histamine-induced itch in theskin (14,15), but also act directly as pruritogens in conjunctiva (16) and inhuman skin when applied via microdialysis bers (17). Upon intradermalinjection, serotonin has been found to elicit pain and a weak itch sensation(18). Recent results suggest that the peripheral eect of serotonin may partlybe due to the release of histamine from mast cells (19). There are also somereports on pruritic eects of mast cell mediators other than histamine likemast cell chymase (20) and other proteinases (21) in human skin. However, no

Figure 2 Relative proportion of mechano-responsive and mechano-insensitiveunmyelinated nociceptors in human skin nerves. About 20% of the nociceptors aremechano-insensitive. Itch units are found only among these mechano-insensitive

bers and comprise about 5% of all nociceptors.

Neurophysiologic Basis of Itch 7

nal decision about the role of these macromolecules in itch induction can bemade.

Acetylcholine has been identied as a pruritic in AD, whereas it inducespain in normal subjects (22). This mechanism could easily explain the itchwhich many AD patients experience when sweating. The role of serotonin inthe pathogenesis of itch is unclear. It might be involved in pruritus seen inpolycythemia vera.

The potency of the main known pruritics can be dened as histamine-prostaglandin E2>acetylcholine, serotonin; in contrast, bradykinin andcapsaicin application basically induce a pure pain sensation. Neurons beingresponsible for the itch sensation would thus be expected to exhibit a gradedresponse according to the pruritic potency of the mediators. In Figure 3,responses of dierent types of C-nociceptors to stimulation with histamine,prostaglandin E2, acetylcholine, serotonin, bradykinin, and capsaicin aredepicted. Only the units showing lasting activation following histamineapplication were also excited by prostaglandin E2. In contrast, we did notobserve any lasting activation of mechanoresponsive nociceptors by hista-mine or by prostaglandin E2. Similarly, all the mechano-insensitive bers,

Figure 3 Intensity of chemically induced activation of dierent classes of C-noci-ceptors.Theunitswerestimulatedwithhistamine(iontophoresis;20mC),prostaglandinE2 (PGE2; 105 M, 20-Al injection), acetylcholine (iontophoresis; 60 mC), serotonin(105M,20-Al injection), bradykinin (105M,20-Al injection), andcapsaicin (0.1%,20-Al injection). (FromRef. 22a.)


which were unresponsive to histamine, were not activated by prostaglandinE2 application. Thus, the response pattern of the histamine-responsive itchunits corresponds to the psychophysically observed pruritic eect of PGE2.Taking into account the histamine sensitivity of these units, indirect activa-tion via histamine released from mast cells has to be considered. Intradermalinjection of PGE2 has been reported to induce only marginal whealing(23,24); however, it provoked a small, albeit signicant, protein extravasationin other studies (25,26). Recently, dermal application of PGE2 via micro-dialysis has been combined with the measurement of local protein extrava-sation and local blood ow (17). In this study, PGE2 did not increase proteinextravasation, even at a concentration of 104 M, but provoked a weak itchsensation and pronounced vasodilation. In contrast, histamine provokesprotein extravasation at lower concentrations as compared to the inductionof itch (27). Thus, rather than being mediated by histamine release, thepruritic eect of PGE2 is most probably due to the direct excitation of his-tamine-positive itch units.

Specic activation of histamine-positive chemonociceptors by PGE2 incombination with the pruritogenic eects of prostaglandins provides a strongargument for a specic neuronal system for the itch sensation, which isseparate from the pain pathway.However, the histamine-positive bersmightnot be classied as itch-specic because they are also excited by purealgogens. The reason why psychophysical algogens provoke pure pain,although they activate itch bers, is most probably a spinal inhibition ofitch by pain (Fig. 4).

Figure 4 Schematic view of response intensity of nociceptors involved in itchprocessing (itch channel) and in pain processing (pain channel). Activation of

the itch channel by algogens like capsaicin is not felt as itch because the painsensation inhibits itch on a spinal cord level.


The itch neurons might therefore be termed itch-selective (28) ratherthan itch-specic. Further support for the specicity, or rather selec-tivity theory, comes from the second-order neurons in the cat that haverecently been recorded. These neurons cannot be excited by mechanicalstimulation, but are activated by histamine iontophoresis with a similar timecourse as compared to the primary aerents (29).

In summary, the pruritic potency of inammatory mediators ischaracterized by their ability to activate histamine-positive mechano-insen-sitive C-nociceptors. However, concomitant activation of mechanosensitiveand mechano-insensitive histamine-negative nociceptors will decrease theitch. Therefore, the itch sensation is based on both activity in the itchchannel and absence of activity in the pain channel.

REFERENCES

1. Torebjork HE, Ochoa J. Pain and itch from C ber stimulation. Soc Neurosci

Abstr 1981; 7:228.2. Bessou P, Perl ER. Responses of cutaneous sensory units with unmyelinated

bers to noxious stimuli. J Neurophysiol 1969; 32:10251043.

3. Torebjork HE. Aerent C units responding to mechanical, thermal and chem-ical stimuli in human non-glabrous skin. Acta Physiol Scand 1974; 92:374390.

4. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specic C-

receptors for itch in human skin. J Neurosci 1997; 17:80038008.5. LaMotte RH, Simone DA, Baumann TK, Shain CN, Alreja M. Hypothesis

for novel classes of chemoreceptors mediating chemogenic pain and itch. In:

Dubner R, Gebhart GF, Bond M, eds. Proceedings of the Vth WorldCongress on Pain. Amsterdam, New York: Elsevier, 1988:529535.

6. Wahlgren CF, Ekblom A. Two-point discrimination of itch in patients with

atopic dermatitis and healthy subjects. Acta Derm-Venereol (Stockh) 1996; 76:4851.

7. Perl ER. Cutaneous polymodal receptors: characteristics and plasticity. Prog

Brain Res 1996; 113:2137.8. Lynn B. Silent nociceptors in the skin. Trends Neurosci 1991; 14:95.9. Meyer RA, Campbell JN. A novel electrophysiological technique for locating

cutaneous nociceptive and chemospecic receptors. Brain Res 1988; 441:8186.

10. Meyer RA, Davis KD, Cohen RH, Treede RD, Campbell JN. Mechanicallyinsensitive aerents (MIAs) in cutaneous nerves of monkey. Brain Res 1991;561: 252261.

11. Schmidt RF, Schaible HG, Messlinger K, Hanesch U, Pawlak M. Silent andactive nociceptors: structure, functions and clinical implications. In: GebhartGF, Hammind DL, Jensen TS, eds. Seattle: IASP Press, 1994:213250.


12. Schmelz M, Schmidt R, Handwerker HO, Torebjork HE. Encoding of burningpain from capsaicin-treated human skin in two categories of unmyelinatednerve bres. Brain 2000; 123:560571.

13. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork HE, HandwerkerHO. Novel classes of responsive and unresponsive C nociceptors in humanskin. J Neurosci 1995; 15:333341.

14. Hagermark O, Strandberg K. Pruritogenic activity of prostaglandin E2. ActaDerm-Venereol 1977; 57:3743.

15. Hagermark O, Strandberg K, Hamberg M. Potentiation of itch and are

responses in human skin by prostaglandins E2 and H2 and a prostaglandinendoperoxide analog. J Invest Dermatol 1977; 69:527530.

16. Woodward DF, Nieves AL, Hawley SB, Joseph R, Merlino GF, Spada CS.

The pruritogenic and inammatory eects of prostanoids in the conjunctiva. JOcul Pharmacol Ther 1995; 11:339347.

17. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M. Prostaglandin E2induces vasodilation and pruritus, but no protein extravasation in atopic der-

matitis and controls. J Am Acad Dermatol 2002; 47:2832.18. Hagermark O. Peripheral and central mediators of itch. Skin Pharmacol 1992;

5:18.

19. Weisshaar E, Ziethen B, Rohl FW, Gollnick H. The antipruritic eect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletionanexperimental study. Exp Dermatol 1999; 8:254260.

20. Hagermark O, Rajka G, Bergvist U. Experimental itch in human skin elicitedby rat mast cell chymase. Acta Derm-Venereol 1972; 52:125128.

21. Rajka G. Latency and duration of pruritus elicited by trypsin in aged pa-

tients with itching eczema and psoriasis. Acta Derm-Venereol 1969; 49: 401403.

22. Vogelgsang M, Heyer G, Hornstein OP. Acetylcholine induces dierent cuta-neous sensations in atopic and non-atopic subjects. Acta Derm-Venereol 1995;

75:434436.22a. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker

HO. Chemical response pattern of dierent classes of C-nociceptors to

pruritogens and algogens. J Neurophysiol 2003; 89:24412448.23. Juhlin L, Michaelsson G. Cutaneous vascular reactions to prostaglandins in

healthy subjects and in patients with urticaria and atopic dermatitis. Acta

Derm-Venereol 1969; 49:251261.24. Kingston WP, Greaves MW. Actions of prostaglandin E2 metabolites on skin

microcirculation. Agents Actions 1985; 16:1314.25. Sabroe RA, Kennedy CT, Archer CB. The eects of topical doxepin on

responses to histamine, substance P and prostaglandin E2 in human skin. Br JDermatol 1997; 137:386390.

26. Sciberras DG, Goldenberg MM, Bolognese JA, James I, Baber NS.

Inammatory responses to intradermal injection of platelet activating factor,histamine and prostaglandin E2 in healthy volunteers: a double blindinvestigation. Br J Clin Pharmacol 1987; 24:753761.


27. Lischetzki G, Rukwied R, Handwerker HO, SchmelzM. Nociceptor activationand protein extravasation induced by inammatory mediators in human skin.Eur J Pain 2001; 5:4957.

28. McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci1992; 15:497501.

29. Andrew D, Craig AD. Spinothalamic lamina 1 neurons selectively sensitive to

histamine: a central neural pathway for itch. Nat Neurosci 2001; 4:7277.


3Pain and Itch

Martin Schmelz

University of Heidelberg, Mannheim, Germany

Hermann O. Handwerker

University of Erlangen, Erlangen, Germany

It is a common experience that the itch sensation can be reduced by the paininduced by scratching.Moreover, the itch sensation is intimately linked to thedesire to scratch, which has recently been visualized as an activation of thepremotor cortical areas in positron emission tomography investigations (13). The inhibition of itch by painful stimuli has been shown experimentallyusing various painful thermal, mechanical, and chemical stimuli. Recently,also electrical stimulation via an array of pointed electrodes, cutaneous eldstimulation, has been successfully used to inhibit itch for several hours in anarea of more than 10 cm around the stimulated site suggesting a central modeof action (4). In line with these results, itch is suppressed inside the secondaryzone of capsaicin-induced mechanical hyperalgesia (5). This central eect ofcapsaicin should be clearly separated from the neurotoxic eect it exertslocally on the nerve bers (6), with both mechanisms inhibiting itch.

The inhibition of itch by pain is not relevant only in a situation withenhanced painful input. The mirror image of this inhibition has signicantimplications: inhibition of pain processing may reduce its inhibitory eect,and thus enhance itch (7). This is of particular relevance for spinally appliedA-opioids which are widely used in pain states and typically cause pruritus.

13

I. INTERACTION OF PAIN AND ITCHPRIMARYAFFERENTS

Although the responses in itch units reect the pruritic potency ofpruritic mediators as shown in an earlier chapter, the strong activation ofthese units by capsaicin and bradykinin seems to contradict a specic roleof these units in itch, since both substances are mainly algogenic and notpruritogenic. An explanation for their ambiguous role in exciting itch andpain-mediating nociceptors may be that their strong excitatory eect onnociceptors involved in pain processing inhibits the neurons of the itchpathway in the course of central nervous processing. It is common knowl-edge that scratching relieves itch. Thus, it can be assumed that activity inmechanosensitive nociceptors suppresses itch. There are, to date, manyreports on itch suppression exerted by painful stimuli. These stimuli includeelectrical stimulation (4) or treatment with capsaicin (5). Recently, also theopposite eect, i.e., increasing of itch sensation by pain reduction, has beenclearly shown (7). On a spinal level, opioids inhibit pain processing andthereby may provoke itch (8). This mechanism is probably the basis for theantipruritic action of opioid antagonists like naloxone or naltrexone (9,10).

The inhibition of itch by painful stimuli has to be taken into consid-eration when activity in itch units is correlated to the pruritic potency ofthe tested mediator (8). As shown in Chapter 2, prostaglandin E2 exclusivelyexcites itch nociceptors, whereas acetylcholine activated a considerablenumber of nonitch nociceptors. Thus, the pruritic eect of PGE2 can beexplained by the activation of itch units and simultaneously the absenceof activity in itch-suppressing nociceptors. Conversely, the activation ofitch units by acetylcholine does not provoke itch because the simulta-neously activated nonitch nociceptors suppress the itch and the perceivedsensation is pain. Accordingly, capsaicin that readily activates itch andnonitch units provokes strong pain and no-itch sensation. Although ourdata support this concept, experimental proof for it can only be obtained inrecordings from second-order neurons.

II. CENTRAL MECHANISMS

Many mechanisms interact with the itch sensation. Temperature changescan either enhance or suppress itch. Cooling can inhibit itch on a centrallevel (11). In addition, histamine-induced activation of nociceptors has beenshown to be temperature-dependent (12), and thus cooling of itching skinsites can reduce the activity of the primary aerents. Note that heating the


skin would consequently lead to exacerbation of itch; however, as soon asthe heating becomes painful, central inhibition of pruritus will counteractthis eect. A summary of peripheral and central eects is given in Table 1(13).

III. CENTRAL SENSITIZATION IN THE PAINAND ITCH SYSTEM

Beyond the direct interaction of pain and itch, a remarkable similarity ofcentral sensitization phenomena exists for the two perceptions. Activity inchemonociceptors subserving the pain sensation will not only lead to an acutepain sensation, but also can sensitize second-order neurons in the dorsal hornleading to increased pain sensitivity (hyperalgesia). Two dierent types ofhyperalgesia can be dierentiated: normally painless touch sensations in theuninjured surroundings of the trauma can be felt as painful stroke-evokedallodynia (see Fig. 1). This type of sensitization requires ongoing activity ofprimary aerent nociceptors. In addition, slightly painful pinprick-likestimulation is felt as more painful in the secondary zone punctuate hyper-algesia. Punctate hyperalgesia does not require ongoing activity in primarynociceptors, but can persist for hours following a trauma (1420).

In itch processing, similar phenomena have been described: touch-evoked pruritus around an itching site has been termed itchy skin or allo-knesis (21,22). Like allodynia, it requires ongoing activity in primary aerentsand is elicited by low threshold mechanoreceptors (Ah bers). Also, moreintense prick-induced itch sensations hyperknesis have been reportedfollowing histamine iontophoresis in healthy volunteers (7) (see Table 2).

Table 1 Environmental Factors and Drugs Attenuating Itch Perception

Eects onperipheral endings Spinal eects

Psychophysicalresult

TemperatureCold Inhibition Inhibition Antipruritic

Warmth Facilitation ? PruriticNoxious heat Nociceptor activation Inhibition Antipruritic

A-Opioids Histamine release Disinhibition Pruriticn-Opioids Histamine release Inhibition AntipruriticCapsaicin Neurotoxic Inhibition Antipruritic

Pain and Itch 15

Figure 1 Schematic view of central sensitization mechanisms in the pain system(upper panel) and in the itch system (lower panel). Under physiological conditions,touch stimuli activate low threshold mechanoreceptive Ah bers resulting in thesensation of touch. Noxious input by histamine-negative chemonociceptors can

sensitize the second-order neurons in the spinal cord. If sensitized, they will also beactivated by low threshold mechanoreceptorsthus, touching the skin will not onlyprovoke the sensation of touch, but also pain (touch-evoked hyperalgesia or allo-

dynia). Similarly, input from Ay nociceptors, which is normally felt as pricking, isfelt more intensely under the condition of central sensitization punctate hyper-algesia. In the lower panel, the corresponding mechanisms are depicted for the itch

system. Ongoing activity of itch units (histamine-positive chemonociceptors) cansensitize second-order itch neurons in the spinal cord. In the sensitized state, theycan be activated by the input from low threshold mechanoreceptors alloknesis or

by the input from Ay bers punctate hyperknesis. DRG=dorsal root ganglion;CNS=central nervous system.


While these considerations appear to be mainly of theoretical relevance,they have an enormous impact on the understanding of clinical itch con-ditions. Under the condition of central sensitization leading to punctuatehyperknesis, normally painful stimuli are felt as itching. This phenomenonhas already been described before for painful electrical stimulation in atopicdermatitis patients (23). Noteworthy also is the fact that acetylcholineprovokes itch instead of pain in patients suering from atopic dermatitis(24,25), indicating that pain-induced inhibition of itch might be compromisedin these patients. As there are amultitude ofmediators andmechanismswhichare potentially algogenic in an inamed skin site (26) and thus could produceitch in a sensitized patient, a therapeutical approach targeting single pruriticmediators does not appear to be promising under this condition. In contrast,the main therapeutical implication of this phenomenon is that a combinationof centrally acting drugs counteracting the sensitization and topically actingdrugs counteracting the inammation should provide the optimum way forantipruritic treatment.

While the exact mechanism and role of central sensitization for itchunder clinical condition still have to be explored, a major role of central

Table 2 Comparison Between Pain and Itch Characteristics

Channel Characteristics

Pain

Acute pain Activity in chemonociceptors(histamine-negative)

Allodyniatouch-evoked pain

. Requires ongoing activity ofhistamine-negative

chemonociceptors. Stimulated by Ah bers

Punctate hyperalgesia

prick-evoked pain

. Does not require ongoing

activity of primary aerents. Stimulated by Ay bers

Itch

Acute itch Activity in chemonociceptors(histamine-positive)

Alloknesistouch-evoked itch

. Requires ongoingactivity of itch bers

. Stimulated by Ah bersPunctate hyperknesis

prick-evoked pain

. Does not require ongoingactivity of primary aerents

. Stimulated by Ay bers?

Pain and Itch 17

sensitization in chronic pain patients is generally accepted. It should benoted that in addition to the similarities between itch and pain in exper-imentally induced secondary sensitization phenomena, there is emergingevidence that a corresponding interaction also exists in chronic pain andchronic itch patients: recently, Baron and colleagues have described that inneuropathic pain patients, histamine iontophoresis, which normally pro-vokes a pure itch sensation, is felt as burning pain (27). Conversely,cutaneous stimulation with acidied solution, which provokes a purelypainful sensation in normal subjects, is felt as itching in atopic dermatitispatients when applied in or close to their eczematous skin (Ikoma andSchmelz, work in progress).

In summary, the latest progress in the understanding of the interactionof pain and pruritus has led to new ideas about central mechanisms of theitch sensation. New therapeutical options are provided especially by theemerging role of spinal opioids for the central itch processing. Furtherclarication of central sensitization phenomena in chronic itch patients willprovide a better understanding of their disease for the patients and will alsoprovide new therapeutical targets for the inhibition of itch.

REFERENCES

1. Hsieh JC, Hagermark O, Stahle Backdahl M, Ericson K, Eriksson L, StoneElander S, Ingvar M. Urge to scratch represented in the human cerebral cortexduring itch. J Neurophysiol 1994; 72:30043008.

2. Drzezga A, Darsow U, Treede R, Siebner H, Frisch M, Munz F, Weilke F,Ring J, Schwaiger M, Bartenstein P. Central activation by histamine-induceditch: analogies to pain processing: a correlational analysis of O-15 H(2)O

positron emission tomography studies. Pain 2001; 92:295305.3. DarsowU,DrzezgaA,FrischM,MunzF,WeilkeF, Bartenstein P, SchwaigerM,

Ring J. Processing of histamine-induced itch in the human cerebral cortex: acorrelation analysis with dermal reactions. J Invest Dermatol 2000; 115:1029

1033.4. HJ Nilsson. Levinsson A, Schouenborg J. Cutaneous eld stimulation (CFS): a

new powerful method to combat itch. Pain 1997; 71:4955.

5. Brull SJ, Atanasso PG, Silverman DG, Zhang J, LaMotte RH. Attenuation ofexperimental pruritus and mechanically evoked dysesthesiae in an area ofcutaneous allodynia. Somatosens Motor Res 1999; 16:299303.

6. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR.Intradermal injection of capsaicin in humans produces degeneration and sub-sequent reinnervation of epidermal nerve bers: correlation with sensory func-

tion. J Neurosci 1998; 18:89478954.7. Atanasso PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, LaMotte RH.


Enhancement of experimental pruritus and mechanically evoked dysesthesiaewith local anesthesia. Somatosens Motor Res 1999; 16:291298.

8. Schmelz M. A neural pathway for itch. Nat Neurosci 2001; 4:910.

9. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR.Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113:12641269.

10. Odou P, Azar R, Luyckx M, Brunet C, Dine T. A hypothesis for endogenousopioid peptides in uraemic pruritus: role of enkephalin. Nephrol Dial Transplant2001; 16:19531954.

11. Bromm B, Scharein E, Darsow U, Ring J. Eects of menthol and cold on his-tamine-induced itch and skin reactions in man. Neurosci Lett 1995; 187:157160.

12. Mizumura K, Koda H. Potentiation and suppression of the histamine responseby raising and lowering the temperature in canine visceral polymodal receptorsin vitro. Neurosci Lett 1999; 266:912.

13. Schmelz M. Itchmediators and mechanisms. J Dermatol Sci 2002; 28:9196.

14. LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia psy-chophysical studies of underlyingmechanisms. JNeurophysiol 1991; 66:190211.

15. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD.

Neurogenic hyperalgesia central neural correlates in responses of spinothalamictract neurons. J Neurophysiol 1991b; 66:228246.

16. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical

hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989;38:99107.

17. LaMotte RH. James Daniel Hardy (19041985). Tribute to a pioneer in pain

psychophysics. Pain, 1986; 27:127130.18. Koltzenburg M, Torebjork HE. Pain and hyperalgesia in acute inammatory

and chronic neuropathic conditions. Lancet 1995; 345:1111.19. Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Dierent patterns of

hyperalgesia induced by experimental inammations in human skin. Brain1994; 117:385396.

20. Koltzenburg M, Lundberg LE, Torebjork HE. Dynamic and static components

of mechanical hyperalgesia in human hairy skin. Pain 1992; 51:207219.21. Heyer G, Ulmer FJ, Schmitz J, Handwerker HO. Histamine-induced itch and

alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm-

Venereol (Stockh) 1995; 75:348352.22. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch

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23. HJ Nilsson. Itch and pain inhibitory mechanisms in humans. Thesis/disserta-tion, Dept. Physiological Sciences, Section for Neurophysiology, UniversityLund, 1999:113.

24. Vogelgsang M, Heyer G, Hornstein OP. Acetylcholine induces dierentcutaneous sensations in atopic and non-atopic subjects. Acta Derm-Venereol1995; 75:434436.

Pain and Itch 19

25. Groene D, Martus P, Heyer G. Doxepin aects acetylcholine induced cuta-neous reactions in atopic eczema. Exp Dermatol 2001; 10:110117.

26. Reeh PW, Kress M. Eects of classical algogens. Semin Neurosci 1995; 7:221

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4Central Neural Mechanisms of Itch

David Andrew

University of Glasgow, Glasgow, Scotland

A. D. Craig

Barrow Neurological Institute, Phoenix, Arizona, U.S.A.

I. INTRODUCTION

The specicity of the sensation of itch has been debated continuously sinceJohannes Muller formulated his theory of specic nerve energies in the 19thcentury. Initial investigations ignored itch, but von Frey (1) identied itchspots in the skin using punctate mechanical stimuli. As these itch spotsseemed to coincide with pain spots, some considered that itch was a sub-liminal version of pain. The question of whether itch is a specic sensation orwhether it arises from weak activation of pain pathways might seem trivial tothose whose experience of itch is conned to the minor annoyance of amosquito bite, but severe, intractable itching that is resistant to conventionaldrugs is a symptom of several systemic diseases including biliary cholestasis,renal failure, HIV infection, and immune disorders.

A. Itch and Pain in Human Studies

Clinical evidence implicating the spinothalamic tract in itch was rst de-scribed by Bickford (2). He observed that spinal lesions in humans (either as aconsequence of disease or cordotomy) that abolished pain and temperature

21

sensations also abolished itch. Similar observations were made by Hyndmanand Wolkin (3), Taren and Kahn (4), and Nathan (5). Pain and itch wereconsidered by some to be related sensations because the sensory dysesthesiaproduced by noxious and pruritic stimuli were similar. After the initial painhas subsided following an injection of capsaicin into the skin, the injection siteis surrounded by an area of allodynia, where pain is evoked by light touch,and an area of hyperalgesia to probing (6). After an intracutaneous injectionof histamine, the injection site is surrounded by an area of alloknesis, wherestroking the skin produces itching. Surrounding this zone is an area ofpunctate hyperknesis, where itch can be evoked with von Frey laments(2,7,8). The early experiments suggested that itch and pain were also trans-mitted by common neural structures, as itch could not be evoked in skin areasthat were rendered hyperalgesic by injury (2,7). This observation does notconrm that itch and pain share common neural substrates; it does, however,demonstrate that itch and pain are sensations that interact (9,10), similar topain and temperature (11). More recent studies (12,13) have shown that itchcan indeed be demonstrated in hyperalgesic skin area as long as the hyper-algesia is mild, but not when the hyperalgesia is intense.

Nonetheless, a specic itch pathway could not be excluded, andseveral independent lines of evidence suggested its existence. Firstly, opiatesrelieve pain, but they often cause itch rather than inhibit it (14); this is par-ticularly true when they are given as part of a spinal anesthetic. Secondly,microneurography experiments in humans identied nerve fascicles whichevoked the sensation of itch when they were electrically stimulated. Increasingthe stimulus frequency increased the intensity of the itching, but did not pro-duce pain (15); conversely, reducing the stimulus frequency at fascicles thatproduced pain when stimulated reduced the intensity of the pain, but did notproduce itch. Thirdly, although some human C-ber polymodal nociceptorsdo respond to histamine (16), the time course and pattern of their activity donot match the well-dened psychophysical judgments of itch (4,17).

B. Physiological Investigation of Itch-Related Neurons

Single-unit recordings from primary aerent bers have been made after theapplication of either histamine or cowhage spicules (Mucuna pruriens) toinvestigate the peripheral neural basis of itch. These reports that have beencovered in Chapter 2 will only be mentioned briey here. An initial studyinvestigated low threshold mechanoreceptive bers and thermoreceptors (18)to gain evidence for the existence of nociceptors as a distinct class of bers,and therefore itch was not investigated. Other studies sought itch-specicbers; however, in essence, all of them failed to provide evidence of elementsspecically excited by itchy substances, and alternative mechanisms involving

Andrew and Craig22

graded intensity encoding (16,19), unique patterns of activity (20), or dier-ential central sorting (21) were suggested. However, many of these studiessuered from the drawback that the search stimuli used would not haveidentied itch-specic units.

Interest in the existence of a specic pathway for itch was revivedfollowing the report by Schmelz et al. (22) describing cutaneous C-bers inhumans that were insensitive to mechanical stimuli, but which showed long-duration excitation that paralleled the psychophysical reports of itch follow-ing the application of histamine into their innervation territories. This was ahighly signicant nding for several reasons. Firstly, the method of iontopho-retic histamine delivery avoided direct injection, which was known to producea mixed sensation of itch and pain (23). Secondly, bers were identied byelectrical stimulation of the skin, whereas previous studies had used natural(usually mechanical) stimulation, eectively biasing against identifying unitsthat were not excited by the search stimulus. Finally, methods were used thatallowed the authors to record from the slowest conducting bers (

frequency following (ve antidromic shocks at 250 Hz) and if collisionoccurred between antidromic and orthodromic impulses. The recording sitesof lamina I STT neurons were marked with electrolytic lesions that wererecovered in histological sections stained with thionin, as were the stimulatingsites in the thalamus.

The receptive properties of each unit that was isolated were tested withthe following stimuli: innocuous brushing, blunt pressure, pinching withforceps, cooling with a beaker of wet ice for up to 30 sec, innocuous warming,and heating to noxious levels for 5 sec. Neuronal responses to these quali-tative stimuli, and also their responses to quantitative stimuli (26), were usedto classify units as one of three functional types: thermoreceptive-specic(COOL or WARM; 2), polymodal nociceptive (HPC, responsive to heat,pinch, and cold), and nociceptive-specic (NS, responsive to pinch and/orheat but not cold). Units that could not be excited by a mechanical or thermalstimulus were provisionally classied as insensitive, and their responses tohistamine were investigated. Histamine was also applied to the receptive eldsof NS and HPC neurons for comparison.

Because the receptive elds of insensitive cells could not be located usingconventional stimuli, histamine (1% in 2.5%methylcellulose gel) was appliedto the area of the skin where background activity in nearby neurons could beelicited. Iontophoresis was used to apply the histamine as this methodproduces a pure sensation of itchwithout any pain (17). To test for nonspeciceects, iontophoresis of the vehicle was performed rst (+1mADC for 3060sec, area 4 mm2) followed by histamine using identical parameters. Histaminewas usually applied at several nonoverlapping sites to test for responsereproducibility and in an attempt to gauge the extent of a neurons receptiveeld. To test the chemical specicity of neurons, some cells were alsoinvestigated by applying mustard oil topically to their receptive eld (50%in ethanol) for 30 sec.

B. Results

Single-unit recordings were made from 190 antidromically identied lamina ISTT neurons with distal hind limb receptive elds. Using natural thermal andmechanical stimuli, we categorized 173 of them (91%) as COOL, WARM,HPC, or NS (26,27). The remaining 17 neurons could not be categorized; ofthese, 14 had no responses at all to any of the thermal or mechanical stimuliused, and 3 showed weak responses to noxious heat stimuli (

We tested each of these 17 insensitive neurons with iontophoreticallyapplied histamine, and we also applied the same current using the vehicle thatdid not contain histamine as a control for each cell. Ten of the neurons wereexcited by histamine and not by the vehicle, with a discharge pattern thatmatched the temporal prole of histamine-sensitive C-ber activity in humansand the accompanying sensations of itch (22): units began to respond after adelay of 13 min, the response peaked within 5 min, and persisted for up to 30min. The response of one histamine-sensitive lamina I STT neuron is shown inFig. 1a, and mean responses to both histamine and vehicle are shown in Fig.1b and c.

We used electrical stimulation with intracutaneous needle electrodes todetermine the conduction velocities of the peripheral bers that providedinputs to the histamine-sensitive lamina I STT neurons in four cases. Intensestimuli (>5 mA, duration up to 10 msec) were required to activate these cells,and they showed only long-latency responses that were time-locked. Thisobservation indicates that the histamine-sensitive neurons were monosynap-tically excited by peripheral C-bers but not by A-bers. The conductionvelocities of the C-ber aerents were very slow (0.50.7 m/sec), slower thanthe velocities of C-bers that drive nociceptive lamina I STT neurons (28).These velocities are consistent with those of the histamine-selective C-bersidentied in humans (22).

For comparison, we tested 16 nociceptive lamina I STTneurons (9NS, 7HPC) with iontophoretically applied histamine and vehicle. Four units (2 NS,2HPC)were not excited at all by either histamine or vehicle. The remaining 12neurons showed phasic excitation from the current applied by iontophoresis.Their ongoing activity typically increased slightly (12 impulses/sec) for ashort time (12 min) following current application with either histamine orvehicle (Fig. 2). These results are consistent with the previous microneuro-graphic observations in humans (16,22).

The novel chemical sensitivity of the histamine-sensitive lamina I STTneurons distinguished them from other types of lamina I STT neurons, butthey were also dierentiated by additional physiological properties, indicat-ing that the histamine-sensitive neurons constitute a unique class of lamina ISTT neurons. The neurons central conduction velocities were signicantlyslower ( p

Figure 1 Histamine- and vehicle-evoked responses from histamine-sensitive laminaI STT neurons. (a) The response of a single neuron to histamine. Top histogram:binned ring rate of the neuron (1-sec bins). The middle trace shows the analogrecord of neuronal activity; the thickening of the baseline in this record during the

iontophoresis (indicated by the lower trace) is due to the current-evoked activation ofseveral neighboring neurons. (b) Mean response of all 10 histamine-sensitive lamina ISTT neurons to histamine application. (c) Mean responses of the same 10 neurons to

vehicle application. Error bars indicate 1 SD. Bin size is 20 sec. (Reproduced fromNature Neuroscience with permission.)

Andrew and Craig26

of nociceptive neurons. The histamine-sensitive neurons were predominatelyactivated from lateral thalamus (the ventral posterior inferior n. and theventral posterior lateral n.), in contrast to NS and HPC neurons, which pro-jected signicantly more often to medial thalamus (n. submedius; p

noxious heat stimulation. These changes in receptive properties could under-lie the sensory phenomena of alloknesis and punctate hyperknesis.We did notapply noxious stimuli during a histamine-evoked discharge to test for inhi-bition of these histamine-sensitive neurons.

We further investigated the chemosensitivity of seven neurons that hadpreviously been tested with histamine by applying topical mustard oil to thecells innervation territory. This chemical algogen produces a sensationof burning pain, and excites most, if not all, C-ber nociceptors in the skin(29,30). Of these seven neurons, four were excited by histamine and theremaining three were not. All three of the histamine unresponsive neuronswere excited by mustard oil for up to 15 min. These units were probablyspecic chemonociceptive neurons. Of the four histamine-sensitive lamina ISTT neurons, two were not excited at all by mustard oil and they were clearlyhistamine-selective. Of the other two cells, one was excited briey by mustardoil, in contrast to its sustained excitation by histamine, and the other wasexcited for >20 min, better than all other cells studied, and its histamineresponse was weak. This neuron might have been a chemonociceptive neuronthat was sensitized by prior noxious heat stimulation of the skin during the

Figure 3 Distinguishing features of histamine-sensitive lamina I STT neurons. (a)Median (horizontal line inside box), 25th and 75th percentiles (box boundaries), andrange (bars) of the central conduction velocities of dierent functional classes of lam-

ina I STT neurons. Figures in parentheses are numbers of neurons. (b) Background(ongoing) activity recorded over a 2-min period for dierent classes of lamina I STTneurons plotted as in (a). None of the histamine-sensitive neurons had ongoing activity

when rst isolated. (c) Comparison of the incidence of histamine-sensitive andnociceptive (NS and HPC) lamina I STT neurons that could be antidromically acti-vated from medial (n. submedius, Med) or lateral (the ventral posterior inferior andventral posterior lateral nuclei, Lat) thalamus. Histamine-sensitive neurons projected

signicantly less frequently to medial thalamus than nociceptive neurons ( p

examination of other cells in that experiment. Thus its weak histamineresponse was in all likelihood an eect of the sensitization.

III. OTHER SPINAL NEURONS EXCITED BY HISTAMINE

The eects of histamine, and also other irritant and noxious chemicals, on theactivity of single rat spinal neurons with unidentied projections have beenstudied by Carstens (31) and Jinks and Carstens (32). The appropriateness ofintracutaneous injection of histamine in rats as a model for itching has beendiscussed in Chapter 5. Initial studies examined cells in the deep dorsal hornthat responded to both innocuous and noxious stimulithe classical widedynamic range neurons. Almost all of the units studied (84%) were activatedby injected histamine. The discharge prole of all of the neurons activatedby histamine showed an adapting time course [time constantf60 sec; (31)],which does notmatch the time course of itch sensation in humans.Most of thecells were also excited by other chemical stimuli including capsaicin, mustardoil, ethanol, serotonin, and nicotine, although not every neuron responded toevery chemical tested, implying some degree of selectivity. However, the re-sponses to dierent chemicals were usually similar, in particular, the capsai-cin-evoked responses were of a magnitude equal to the histamine-evokedresponses. These wide dynamic range neurons are considered bymany to beimportant in pain, as they increase their discharge as stimulus intensityincreases from innocuous to noxious. A role in itch for these neurons mighthave been suggested if the histamine-evoked discharges were within a range ofring rates that spanned the innocuous to noxious range. However, theirresponses did not dierentiate a noxious chemical from a pruritic one whenthe sensations produced by them are very dierent (itching vs. burning pain).The failure to observe any evidence of coding of noxious and pruritic stimuli inthe discharge of the neurons suggests that these modality ambiguous neuronsare unlikely to be involved in the sensory-discriminative aspects of itching.

A later study addressed the responses of supercial dorsal horn neurons(32) to histamine and other chemicals. Neurons were identied by the pres-ence of ongoing (background) activity, classied using mechanical and heatstimuli, and their chemical sensitivity was investigated by injecting histamineand other irritant chemicals (capsaicin, mustard oil, and nicotine) intra-cutaneously into their receptive elds. Relying on background activity toidentify cells will have automatically excluded the possibility of recordingfrom neurons without spontaneous activity, which would have included thehistamine-sensitive lamina I STT neurons identied in the cat. Like the deepdorsal horn neurons, the typical response of supercial dorsal horn neurons tohistamine was adaptive, but the time constant of the supercial neurons was

Central Neural Mechanisms of Itch 29

slightly longer than that of the deep cells (meanf92 sec). Additionally, almostall of the cells that responded to histamine were also activated by the otherchemicals, as well as being responsive to nociceptive and/or non-nociceptivephysical stimuli. Thus, like the deep dorsal horn neurons, supercial noci-ceptive neurons with unidentied projections do not distinguish a pruriticstimulus from a nociceptive stimulus.

The eects of injected histamine on supercial and deep dorsal hornneurons in the rat are similar to those of iontophoretic histamine on noci-ceptive lamina I STT neurons in the cat, i.e., a brief phasic excitation thatquickly declines to background levels. This is to be expected based on theweak histamine sensitivity of primary aerent nociceptors (see Chapters 2 and3). Injected histamine is known to cause a mixed sensation of itch and pain(22), and the histamine-evoked excitation of nociceptive neurons likelyreects the role of these cells in pain rather than in itch.

IV. THALAMO-CORTICAL PATHWAYS FOR ITCH

Functional brain imaging studies have identied cortical regions activated byitch in humans. The rst investigation (33) used intracutaneously injectedhistamine to evoke itch, which can produce both pain and itch (see previoustext). Notwithstanding this, the contralateral anterior cingulate cortex (area24) was the most strongly activated brain region. Other motor-relatedstructures activated included the ipsilateral inferior parietal cortex of theposterior parietal cortex, the supplemental motor area bilaterally, and theipsilateral dorsolateral prefrontal cortex. Activation of the anterior cingulate(limbic motor cortex) was interpreted as being the representation of the urgeto scratch, whereas the other cortical areas are involved in the integrationand execution of target-orientated voluntary movements. A later study wherehistamine was pricked into the skin (34) conrmed the activation in many ofthe same motor regions, and also described correlations between itchunpleasantness/intensity and activation in the contralateral insula, primarysomatosensory cortex, and supplemental motor areas bilaterally.

The activation of these cortical regions, particularly anterior cingulatecortex and insular cortex, corresponds with the functional anatomy ofascending lamina I axons (35). In primates, there is a dedicated pain-and-temperature (and presumably itch) nucleus in the posterior thalamus(VMpo) (3638) that receives modality-specic information only from lami-na I neurons. This nucleus projects topographically to insular cortex, but italso projects collaterals to area 3a in primary somatosensory cortex (S I).Other diencephalic targets of ascending lamina I axons are the ventrocaudalaspect of the mediodorsal nucleus (MDvc) and the ventral posterior inferior

Andrew and Craig30

nucleus (VPI) (35,36). Neurons in MDvc project to area 24 in the anteriorcingulate cortex, whereas those in VPI project to secondary somatosensorycortex (S II). Thus the activation of the insula and the anterior cingulate cortexin human imaging studies of itch is likely relayed by lamina I STTneurons thatterminate in VMpo and MDvc, consistent with the proposed interoceptiverole of this pathway. Substantial species dierences exist between cat andmonkey as the lamina I projection to anterior cingulate in cats is probablyrelayed through neurons in the ventral periphery of the ventral posteriornucleus (VPI and VPL) (39,40), rather than MDvc. Nonetheless, the combi-nation of results fromphysiological studies in cats, tracing studies inmonkeys,and imaging studies in humans supports the concept of a dedicated lamina Ispino-thalamo-cortical pathway for itch. Further experiments in nonhumanprimates will be needed to conrm this prediction.

V. NOVEL THERAPIES FOR ITCH

Our ndings provide strong evidence supporting the specic nature of thesensation of itch. Previous physiological data were insucient to excludecompeting hypotheses of graded intensity, unique temporal patterns, ordierential sorting (16,21,41) until the demonstration of itch-specicprimary aerent C-bers (22). Our observations conrm that the responseprole of these bers is maintained in a distinct population of lamina I STTneurons, which have unique physiological properties. Another group ofneurons was selectively excited by mustard oil, and these cells are likely tobe important in chemogenic pain. Both results conrm theoretical predictionsbased on human psychophysical studies (6,41,42).

The identication of a dedicated central neural pathway for itch oersthe opportunity to identify novel targets for the development of new anti-pruritic agents. Nociceptive and thermoreceptive lamina I neurons are phys-iologically and anatomically unique. That is, the shape of a neurons soma andits proximal dendrites is a characteristic of its function (24). Thus pyramidal-shaped cells are cooling-specic thermoreceptive neurons, fusiform-shapedcells are usually nociceptive-specic neurons, and multipolar cells are typi-cally polymodal nociceptive neurons. Thermoreceptive and nociceptive lam-ina I STT neurons also have dierent patterns of termination in the thalamus(43). We hypothesize that because the histamine-sensitive lamina I STT neu-rons we identiedwere dierentiated by their distinct physiological character-istics, they will also have dening anatomical characteristics. Althoughhistamine-sensitive neurons have not yet been intracellularly labeled, theirincidence (f5%, 10/190) coincides with the incidence of lamina I STT neu-rons that have shapes categorized as unclassied, that is, neither pyramidal,


fusiform, nor multipolar (44). The ability to determine histologically whichlamina I STT neurons were histamine-sensitive could lead to, using DNAmicroarray techniques, the identication of novel genes and proteinsexpressed by those neurons alone. These markers could be used as targetsfor drug discovery.

ACKNOWLEDGMENTS

This chapter is supported by the Royal Society of Edinburgh, the NationalInstitutes of Health (NS 25616), and the Atkinson Pain Research Fundadministered by the Barrow Neurological Foundation.

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