Itch Basic Mechanisms and Therapy doc

Professor and Chair, Department ofPhysiology and Experimental Pathophysiology, University of Erlangen,Erlangen, GermanyEngland and Liver Diseases, Academic Medical Center, Amsterdam, The

tion, shall be liable for any loss, damage, or liability directly or indirectly caused oralleged to be caused by this book The material contained herein is not intended toprovide specific advice or recommendations for any specific situation.

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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

Irritant Contact Dermatitis, edited by Edward M Jackson and Ronald Goldner

Alan R Shalita

Leveque and Pierre G Agache

Retinoids: Progress in Research and Clinical Applications, edited by Maria A Livrea and Lester Packer

Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice

Oxidative Stress in Dermatology, edited by Jurgen Fuchs and Lester Packer

and Thomas Krieg

and Thomas Schwarz

and Robert C Wallach

Jacobs and Lexie Nall

Charles J McDonald

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

Itch: Basic Mechanisms and Therapy, edited by Gil Yosipovitch, Malcolm

W Greaves, Alan 8 Fleischer, Jr., and Francis McGlone

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

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 more

to pruritus than scratching the surface

M W G

To my wonderful and patient wife, Anne

A B F

For all those who suffer still, in the hope that our growing knowledge

of the mechanisms will enhance our therapies

F M

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 variety

of disciplines have come to recognize both the importance of skin in 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

fun-With these factors in mind, we have undertaken to develop this series ofbooks specifically 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 volumes

in the series will ultimately prove to be valuable additions to the gist’s library

dermatolo-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 field We trust that this volumewill be of broad interest to scientists and clinicians alike

Alan R ShalitaSUNY Health Science Center

Brooklyn, New York

v

You know that I would cut off

My hands to help you

But if I did I wouldn’t have

Anything to scratch with

And then I’d be of

No use at all

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 temic diseases

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

vii

define novel pathways for itch Improved understanding of the 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 as microdialysis 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.

pathophysi-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 pathogenesis

of itching

Thomas A Luger, M.D.Professor and ChairmanDepartment of DermatologyUniversity Clinics Mu¨nster

Mu¨nster, Germany

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

of itch and has confirmed the distinctiveness of itch pathways in comparisonwith pain pathways

We were motivated to work on this book by consideration of patientsafflicted 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 first 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

ix

information for both dermatologists and nondermatologists who treat itch,

as well as for researchers in the field of neurophysiology and pharmacology.The organization of the chapters reflects our views as to how the reader canbest utilize these materials The book has six parts Part I contains a pro-posed clinical classification 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 different 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 field.While efforts 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 scientific and clinical communities

Gil YosipovitchMalcolm W GreavesAlan B Fleischer, Jr.Francis McGlone

Foreword Thomas A Luger vii

Gil Yosipovitch and Malcolm W Greaves

Martin Schmelz and Hermann O Handwerker

Martin Schmelz and Hermann O Handwerker

David Andrew and A D Craig

Earl Carstens and Yasushi Kuraishi

xi

6 Histamine-Induced Discriminative and Affective

Francis McGlone, Roman Rukwied, Matt Howard,

and David Hitchcock

Ulf Darsow, Alexander Drzezga, and Johannes Ring

Dieter Metze

Tsugunobu Andoh and Yasushi Kuraishi

Paul Lorenz Bigliardi and Mei Bigliardi-Qi

Jun Utsumi, Yuko Togashi, Hideo Umeuchi, Kiyoshi Okano,

Toshiaki Tanaka, and Hiroshi Nagase

Roman Rukwied, Melita Dvorak, Allan Watkinson,

and Francis McGlone

Jens Schiersing Thomsen

Jens Schiersing Thomsen

Martin Schmelz

16 Measuring Nocturnal Scratching in Atopic Dermatitits 161Toshiya Ebata

Gil Yosipovitch

Gil Yosipovitch

Thomas Mettang, Dominik Mark Alscher,

and Christiane Pauli-Magnus

Nora V Bergasa and E Anthony Jones

Maria I Duque, Gil Yosipovitch, and P Samuel Pegram

Gil Yosipovitch, Rashel Goodkin, Ellen Mary Wingard,

and Jeffrey D Bernhard

Ulf Darsow and Johannes Ring

Robert D Nelson

Yung-Hian Leow and Gil Yosipovitch

Sonja Sta¨nder and Dieter Metze

27 Prospects for a NovelK-Opioid Receptor Agonist,

Hiroo Kumagai, Shigeaki Matsukawa, Jun Utsumi,

and Takao Saruta

Sonja Sta¨nder and Dieter Metze

Extract of the Amazonian Ethnomedicine Sangre de

Mark J S Miller, Brian K Reuter, John L Wallace,

Keith A Sharkey, and Paul Bobrowski

Immunomodulators: A New Approach for Patients with

Uwe Gieler, Volker Niemeier, Burkhard Brosig, and Jo¨rg

Kupfer

Elia E Psouni

Yuval Melamed and Gil Yosipovitch

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

Medical and Pharmaceutical University, Toyama, Japan

Neuro-science and Biomedical Systems, University of Glasgow, Glasgow, Scotland

Diseases, Department of Medicine, College of Physicians and Surgeons,Columbia University, New York, New York, U.S.A

Uni-versity of Massachusetts Medical School, Worcester, Massachusetts, U.S.A

Basel University Hospital, Basel, Switzerland

Basel University Hospital, Basel, Switzerland

Ari-zona, U.S.A

xv

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

Behavior, University of California, Davis, Davis, California, U.S.A

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

Technical University of Munich, Munich, Germany

of Nuclear Medicine, Technical University of Munich, Munich, Germany

Univer-sity School of Medicine, Winston-Salem, North Carolina, U.S.A

Man-chester, ManMan-chester, England

Jikei University School of Medicine, Tokyo, Japan

Dermatol-ogy, Wake Forest University School of Medicine, Winston-Salem, NorthCarolina, U.S.A

Psychosomatics and Psychotherapy, Justus-Liebig University, Giessen, many

Burling-ton, Massachusetts, U.S.A

Depart-ment of Dermatology, University of London, London, England, and pore General Hospital, Singapore, Republic of Singapore

Singa-Hermann O Handwerker, M.D., Ph.D Professor and Chair, Department ofPhysiology and Experimental Pathophysiology, University of Erlangen,Erlangen, Germany

England

and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands

Medi-cine, Keio University School of MediMedi-cine, Tokyo, Japan

Uni-versity, Giessen, Germany

Faculty of Pharmaceutical Sciences, Toyama Medical and PharmaceuticalUniversity, Toyama, Japan

Dermatol-ogist, National Skin Centre, Singapore, Republic of Singapore

Inagi Municipal Hospital, Tokyo, Japan

Uni-lever Research and Development, Wirral, England, and Associate Director ofthe Center for Cognitive Neuroscience, University of Wales, Bangor, Wales

Aviv Faculty of Medicine, Lev-Hasharon Mental Health Center, Natania,Israel

Gen-eral Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart,Germany

Mu¨nster, Mu¨nster, Germany

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

Toray Industries, Inc., Kamakura, Kanagawa, Japan

Depart-ment of Surgery, Regions Hospital, St Paul, Minnesota, U.S.A

for Psychosomatics and Psychotherapy, Justus-Liebig University, Giessen,Germany

Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura,Kanagawa, Japan

Toxicology, University Hospital Zurich, Zurich, Switzerland

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

Depart-ment of Physiological Sciences, Lund University, Lund, Sweden

Sciences, Albany Medical College, Albany, New York, U.S.A

of Dermatology and Allergy Biederstein, Technical University of Munich,Munich, Germany

Eng-land

Nephrol-ogy and Hypertension, Keio University School of Medicine, Tokyo, Japan

University of Heidelberg, Mannheim, Germany

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

Mu¨nster, Germany

Pharmaceut-ical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa,Japan

Gen-tofte University Hospital, Copenhagen, Denmark

Indus-tries, Inc., Kamakura, Kanagawa, Japan

Pharma-ceutical Research Laboratories, Toray Industries, Inc., Kamakura, gawa, Japan

Plan-ning Department, Toray Industries, Inc., Tokyo, Japan

Medicine, University of Calgary, Calgary, Alberta, Canada

Der-matology, University Hospital, Lund, Sweden

England

Der-matology, Department of Social Medicine, University of Heidelberg, berg, Germany

Massachusetts Medical School, Worcester, Massachusetts, U.S.A

Neuro-science, Department of Dermatology, and Neuroscience Center, Wake ForestUniversity School of Medicine, Winston-Salem, North Carolina, U.S.A

Definitions 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 definition of itch first proposed by Samuel Hafenreffer (1) 340

still widely used; however, as indicated by Savin (2), it is unsatisfactorybecause unpleasant is a subjective adjective and is not a descriptor capable

of precise definition We also wish to point out that many subjects rub but

do not scratch in response to itch The well-known sign of polished 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 definition of itch remains elusive, at least to

finger-us, it is worth attempting operational definitions of different types of itch forthe assistance of those working in this difficult field

As with any other subjective symptom, definitions pose problems Theyserve as an operational framework and we do not intend to constrain updates

in the future The terms and definitions are not meant to be a comprehensiveglossary but rather a standard glossary for people who work in the field 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 inflammation or injury of body tissue and activation

of pruritoceptive fibers at the site of local tissue damage This alters the 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

re-Itch that persists for weeks, months, or years is not classified underthis category

that 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 patient’ssocial life and even lead to suicide as in patients with chronic pain.Because chronic itch is unrelenting, affective 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 inflammation and thereby shorten itch

course of medical practice A more detailed definition for intractable itch is

‘‘a 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 reasonable

when we state that chronic itch is treatable It is important to acknowledgethat such patients are encountered weekly in dermatology clinics, and they

do suffer In these cases, a more holistic approach is required by an disciplinary team, with the involvement of both patients and their families

inter-It integrates pharmacologic and nonpharmacologic treatment with neededpsychotherapy and rehabilitation

does 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 woolfibers in a noninvolved area surrounding an itching lesion Another common

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

in-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 and

in neuropathic itch, but there are as yet no reported instances of suchdemonstrations

Recently, a definition of different 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

dryness, or other skin damage Examples include itch due to xerosis, caria, insect bite reactions, and scabies, to name a few

the afferent pathway Examples include postherpetic neuralgic itch, ioradial itch, itch associated with cerebral vascular events in the CNS, itchassociated with multiple sclerosis and brain tumors (see Chapter 22)

of neural pathology, exemplified by itch of cholestasis due to the action ofopioid neuropeptides on opioid receptors (see Chapter 10)

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 as

a neurogenic itch involved

REFERENCES

1 Hafenreffer S Nosodochium, in quo cutis, eique adaerentium partium, affectusomnes, singulari methodo, et cognoscendi e curandi fidelisime traduntur Ulm:Ku¨hnen, 1660:98–102

2 Savin J How should we define itching? J Am Acad Dermatol 1998; 39:268–269

3 Simone DA, Alreja M, LaMotte RH Psychophysical studies of the itch sensation

and itchy skin (‘‘alloknesis’’) produced by intracutaneous injection of histamine.Somatosens Mot Res 1991; 8:271–279.

4 Heyer G, Groene D, Martus P Efficacy of naltrexone on acetylcholine-inducedalloknesis in atopic eczema Exp Dermatol 2002; 11:448–455

5 Twycross R, Greaves MW, Handwerker H, et al Itch: scratching more than thesurface Q J Med 2003; 96:7–26

6 Yosipovitch G, Greaves M, Schmelz M Itch Lancet 2003; 361:690–694

7 Bernhard JD Neurogenic pruritus and strange sensations In: Bernhrad JD, ed.Itch Mechanisms and Management of Pruritus New York: McGraw Hill,1994:185–202

Neurophysiologic Basis of Itch

of itch Increasing the stimulation frequency increased the magnitude of pain

or 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) According

to these results, firing frequency in nociceptors cannot account for thedifferentiation 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-fibers, the mechanoheat

5

nociceptors (CMH or ‘‘polymodal nociceptors’’), which have been 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 application

exten-in the skexten-in Recently, C-nociceptors have been discovered among 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’’ fibers 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 fibers, 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

mechano-Figure 1 The upper panel shows instantaneous discharge frequency of a and heat-insensitive C-fiber (CMiHi) in the superficial peroneal nerve followinghistamine iontophoresis (marked as open circles in the diagram) The unit was notspontaneously active before histamine application, but continued to fire for about 15min further (not shown in the diagram).The lower panel shows average itch magnituderatings 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.)

mechano-chemical stimuli They have been termed‘‘polymodal’’ nociceptors (7) Theremaining 20% do not respond to mechanical stimulation These fibers havebeen classified as ‘‘silent’’ or ‘‘sleeping’’ nociceptors (8–11) They can bereadily activated by chemical stimuli (12) and can also be sensitized tomechanical stimulation under inflammatory conditions (12,13) Units with

a 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 fibers (17) Upon intradermalinjection, serotonin has been found to elicit pain and a weak itch sensation(18) Recent results suggest that the peripheral effect of serotonin may partly

be due to the release of histamine from mast cells (19) There are also somereports on pruritic effects 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-insensitivefibers and comprise about 5% of all nociceptors

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

Acetylcholine has been identified 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 defined as 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 different 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 fibers,

histamine-Figure 3 Intensity of chemically induced activation of different classes of ceptors The units were stimulated with histamine (iontophoresis; 20 mC), prostaglandinE2 (PGE2; 10
5M, 20-Al injection), acetylcholine (iontophoresis; 60 mC), serotonin(10
5M, 20-Al injection), bradykinin (10
5M, 20-Al injection), and capsaicin (0.1%, 20-

C-noci-Al injection) (From Ref 22a.)

which were unresponsive to histamine, were not activated by prostaglandinE2 application Thus, the response pattern of the histamine-responsive‘‘itch’’units corresponds to the psychophysically observed pruritic effect 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 significant, protein extravasation

in other studies (25,26) Recently, dermal application of PGE2 via dialysis has been combined with the measurement of local protein extrava-sation and local blood flow (17) In this study, PGE2 did not increase proteinextravasation, even at a concentration of 10
4M, but provoked a weak itchsensation and pronounced vasodilation In contrast, histamine provokesprotein extravasation at lower concentrations as compared to the induction

micro-of itch (27) Thus, rather than being mediated by histamine release, thepruritic effect of PGE2 is most probably due to the direct excitation of his-tamine-positive‘‘itch’’ units

Specific activation of histamine-positive chemonociceptors by PGE2 incombination with the pruritogenic effects of prostaglandins provides a strongargument for a specific neuronal system for the itch sensation, which isseparate from the pain pathway However, the histamine-positive fibers mightnot be classified as ‘‘itch-specific’’ because they are also excited by purealgogens The reason why psychophysical algogens provoke pure pain,although they activate‘‘itch’’ fibers, 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 ofthe‘‘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-specific.’’ Further support for the ‘‘specificity,’’ 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 afferents (29).

In summary, the pruritic potency of inflammatory 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.’’

chem-4 Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo¨rk HE Specific receptors for itch in human skin J Neurosci 1997; 17:8003–8008

C-5 LaMotte RH, Simone DA, Baumann TK, Shain CN, Alreja M Hypothesisfor 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, 1988:529–535

6 Wahlgren CF, Ekblom A Two-point discrimination of itch in patients withatopic dermatitis and healthy subjects Acta Derm-Venereol (Stockh) 1996; 76:48–51

7 Perl ER Cutaneous polymodal receptors: characteristics and plasticity ProgBrain Res 1996; 113:21–37

8 Lynn B ‘Silent’ nociceptors in the skin Trends Neurosci 1991; 14:95

9 Meyer RA, Campbell JN A novel electrophysiological technique for locatingcutaneous nociceptive and chemospecific receptors Brain Res 1988; 441:81–86

10 Meyer RA, Davis KD, Cohen RH, Treede RD, Campbell JN Mechanicallyinsensitive afferents (MIAs) in cutaneous nerves of monkey Brain Res 1991;561: 252–261

11 Schmidt RF, Schaible HG, Messlinger K, Hanesch U, Pawlak M Silent andactive nociceptors: structure, functions and clinical implications In: Gebhart

GF, Hammind DL, Jensen TS, eds Seattle: IASP Press, 1994:213–250

12 Schmelz M, Schmidt R, Handwerker HO, Torebjo¨rk HE Encoding of burningpain from capsaicin-treated human skin in two categories of unmyelinatednerve fibres Brain 2000; 123:560–571.

13 Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjo¨rk HE, Handwerker

HO Novel classes of responsive and unresponsive C nociceptors in humanskin J Neurosci 1995; 15:333–341

14 Ha¨germark O, Strandberg K Pruritogenic activity of prostaglandin E2 ActaDerm-Venereol 1977; 57:37–43

15 Ha¨germark O, Strandberg K, Hamberg M Potentiation of itch and flareresponses in human skin by prostaglandins E2 and H2 and a prostaglandinendoperoxide analog J Invest Dermatol 1977; 69:527–530

16 Woodward DF, Nieves AL, Hawley SB, Joseph R, Merlino GF, Spada CS.The pruritogenic and inflammatory effects of prostanoids in the conjunctiva JOcul Pharmacol Ther 1995; 11:339–347

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; 47:28–32

18 Ha¨germark O Peripheral and central mediators of itch Skin Pharmacol 1992;5:1–8

19 Weisshaar E, Ziethen B, Rohl FW, Gollnick H The antipruritic effect of a HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion—anexperimental study Exp Dermatol 1999; 8:254–260

5-20 Ha¨germark O, Rajka G, Bergvist U Experimental itch in human skin elicited

by rat mast cell chymase Acta Derm-Venereol 1972; 52:125–128

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Pain 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 (1–3) 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 fieldstimulation,’’ has been successfully used to inhibit itch for several hours in anarea of more than 10 cm around the stimulated site suggesting a central mode

of action (4) In line with these results, itch is suppressed inside the secondaryzone of capsaicin-induced mechanical hyperalgesia (5) This central effect ofcapsaicin should be clearly separated from the neurotoxic effect it exertslocally on the nerve fibers (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 significantimplications: inhibition of pain processing may reduce its inhibitory effect,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 ITCH—PRIMARY

AFFERENTS

Although the responses in ‘‘itch’’ units reflect the pruritic potency ofpruritic mediators as shown in an earlier chapter, the strong activation ofthese units by capsaicin and bradykinin seems to contradict a specific role

of 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 effect 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 effect, 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 E2exclusivelyexcites ‘‘itch’’ nociceptors, whereas acetylcholine activated a considerablenumber of nonitch nociceptors Thus, the pruritic effect of PGE2 can beexplained by the activation of‘‘itch’’ units and simultaneously the absence

of activity in itch-suppressing nociceptors Conversely, the activation of

‘‘itch’’ units by acetylcholine does not provoke itch because the 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

simulta-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 afferents 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 effect A summary of peripheral and central effects is given in Table 1(13).

III CENTRAL SENSITIZATION IN THE PAIN

AND 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 different types ofhyperalgesia can be differentiated: 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 afferent 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 (14–20)

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

touch-Table 1 Environmental Factors and Drugs Attenuating Itch Perception

Effects onperipheral endings Spinal effects

PsychophysicalresultTemperature

Cold Inhibition Inhibition AntipruriticWarmth Facilitation ? PruriticNoxious heat Nociceptor activation Inhibition AntipruriticA-Opioids Histamine release Disinhibition Pruriticn-Opioids Histamine release Inhibition AntipruriticCapsaicin Neurotoxic Inhibition Antipruritic

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 fibers resulting in thesensation of touch Noxious input by histamine-negative chemonociceptors cansensitize the second-order neurons in the spinal cord If sensitized, they will also beactivated by low threshold mechanoreceptors—thus, 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 itchsystem 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 fibers ‘‘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 suffering from atopic dermatitis(24,25), indicating that pain-induced inhibition of itch might be compromised

in these patients As there are a multitude of mediators and mechanisms whichare potentially algogenic in an inflamed 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 combination

of centrally acting drugs counteracting the sensitization and topically actingdrugs counteracting the inflammation 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)Allodynia

‘‘touch-evoked pain’’

. Requires ongoing activity of

histamine-negativechemonociceptors

. Stimulated by Ah fibersPunctate hyperalgesia

‘‘prick-evoked pain’’

. Does not require ongoingactivity of primary afferents

. Stimulated by Ay fibersItch

Acute itch Activity in chemonociceptors

(histamine-positive)Alloknesis

‘‘touch-evoked itch’’

. Requires ongoingactivity of‘‘itch’’ fibers

. Stimulated by Ah fibersPunctate hyperknesis

‘‘prick-evoked pain’’

. Does not require ongoingactivity of primary afferents

. Stimulated by Ay fibers?

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 acidified 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 interaction

of 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 Furtherclarification 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

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