news & views
examination.6 notably, pulmonary abnor-
malities are frequently reported in post-
mortem and antemortem examinations
of suDeP or near-suDeP patients. 7,8
respiratory compromise is also a crucial
event leading to sudden death in DBa
mice, and can be prevented by administer-
ing 5-hydroxytryptamine (5-Ht) receptor
agonists and 5-Ht reuptake inhibitors,5
consistent with experimental and clinical
data supporting a role for the serotonergic
system in the control of central respiration.9
notably, levels of cerebrospinal monoamine
metabolites such as 5-hydroxyindolacetic
acid, which reflect serotonergic activity,
were found to be decreased in the epileptic
baboon, 10 confirming that the potential
links between the serotonergic system and
the pathophysiology of suDeP are worthy
of further exploration.
the ultimate aim of this research should
be the identification of prevention strategies
and effective therapies. the attainment of
this goal, however, raises important practi-
cal and ethical issues. in particular, while
the ethical principle of individual autonomy
entails the patient’s right to know about
his or her own medical condition and
prognosis, the patient’s right to not know
about certain aspects of a medical condi-
tion should also be respected. thus, the
american epilepsy society and the epilepsy
Foundation Joint task Force on suDeP
suggest individualization of information
according to each patient’s suDeP risk and
the cultural and educational background of
families and caregivers.3
Further research into suDeP will require
an interdisciplinary approach and an inter-
national collaborative effort, combining
basic research (at the live animal, organ, and
cellular and molecular levels) with clini-
cal research. Clinicians (neurologists and
cardiologists) and basic scientists (neuro-
physiologists, cardiovascular physiologists,
geneticists and molecular biologists) should
be involved in this effort. with these aims in
mind, mortemus (mortality in epilepsy
monitoring unit study), an international
collaboration between different european
epilepsy centers, is currently collecting as
many cases as possible of suDeP occurring
during video-eeG monitoring.
animal and clinical studies will, hopefully,
lead to a better understanding of the mul-
tiple factors involved in suDeP, and to pre-
ventive strategies focused on seizure control,
therapy optimization, and education.
640 | DECEMBER 2009 | voluME 5
Muscular and Neurodegenerative Diseases
Unit, Giannina Gaslini Institute, University of
Genoa, Genoa, Italy (P. Striano, F. Zara).
Correspondence: P. Striano, Muscular and
Neurodegenerative Diseases Unit, Giannina
Gaslini Institute, University of Genoa, Largo
Gaslini 5, 16147 Genoa, Italy
pstriano@email.it
doi:10.1038/nrneurol.2009.190
Competing interests
The authors declare no competing interests.
1. surges, R., Thijs, R. D., Tan, H. L. &
sander, J. w. sudden unexpected death in
epilepsy: risk factors and potential
pathomechanisms. Nat. Rev. Neurol. 5,
492–504 (2009).
2. nashef, L. sudden unexpected death in
epilepsy: terminology and definitions. Epilepsia
38 (suppl. 11), 6–8 (1997).
3. so, e. L. et al. Report of the American epilepsy
society and the epilepsy Foundation Joint Task
Force on sudden Unexplained Death in
epilepsy. Epilepsia 50, 917–922 (2009).
4. Johnston, s. C., siedenberg, R., Min, J. K.,
Jerome, e. H. & Laxer, K. D. Central apnea and
PaIn
Itch without pain—a labeled line
for itch sensation?
Hermann O. Handwerker and Martin Schmelz
neurons that seem to be specifically involved in relaying pruritogenic
sensory information to the brain have been identified in lamina I of
the spinal cord. are these neurons part of the long sought-after neural
pathway for itch? The answer to this question could be important for the
development of antipruritogenic drugs.
Chronic itch is a debilitating condition, and
no effective treatments are currently avail-
able to alleviate the symptoms. sensations
of chronic itch are well known to be caused
by a large number of diseases and also by
some treatments. relatively little is known,
however, about the neurobiology of itch,
especially when compared with other
sensory modalities such as nociception
and proprioception. owing to ambiguity
surrounding the mechanisms underlying
pruritogenic sensory transduction, and
the fact that previous studies suggest that
itch and pain share many similarities, these
two distinct sensations were thought to
share common neural pathways. a study
published in Science, however, now provides
© 2009 Macmillan Publishers Limited. All rights reserved
acute cardiac ischemia in a sheep model of
epileptic sudden death. Ann. Neurol. 42,
588–594 (1997).
5. Tupal, s. & Faingold, C. L. evidence supporting
a role of serotonin in modulation of sudden
death induced by seizures in DBA/2 mice.
Epilepsia 47, 21–26 (2006).
6. szabó, C. A. et al. Mortality in captive
baboons with seizures: a new model for
sUDeP? Epilepsia 50, 1995–1998
(2009).
7. Leestma, J. e., Annegers, J. F. & Brodie, M. J.
sudden unexplained death in epilepsy:
observations from a large clinical
development program. Epilepsia 38, 47–55
(1997).
8. Pezzella, M. et al. severe pulmonary congestion
in a near-miss at the first seizure: further
evidence for respiratory dysfunction in sudden
unexpected death in epilepsy. Epil. Behav. 14,
701–702 (2009).
9. Ling, L. et al. Chronic intermittent hypoxia
elicits serotonin-dependent plasticity in the
central neural control of breathing. J. Neurosci.
21, 5381–5388 (2001).
10. szabó, C. A. et al. Cerebrospinal fluid levels of
monoamine metabolites in the epileptic
baboon. Epilepsia 49 (suppl. 7), 473–474
(2008).
evidence that pruritogenic information is
conveyed to the brain by a neural pathway
that is distinct from identified nociceptive
neural pathways. this information could
prove useful in the development of novel
antipruritic therapies.
in their study, sun et al. report the effects
of selectively ablating a group of second-
order neurons located in lamina i of the
mouse spinal cord. these neurons express the
gastrin-releasing peptide receptor (GrPr),
which has been identified as an itch-specific
biomarker.1 GrPr+ neurons were ablated
by intrathecal administration of bombesin–
saporin, a complex consisting of a toxin
coupled to bombesin that specifically kills
GrPr-expressing neurons. this treatment
www.nature.com/nrneurol

substantially attenuated itch-related scratch- brought into contact with the superficial
ing behavior in a dose-dependent manner.
the pruritogenic effects of various agents,
including histamine-dependent pruritogenic
agents (histamine, 5-hydroxytryptamine and
compound 48/80) and partially histamine-
dependent pruritic agents (endothelin-1 and
chloroquine—an antimalarial drug that can
cause pruritus in man),2 were ameliorated
in these mice. to ascertain whether GrPr+
neurons are essential
neural substrates for the
sensation of chronic itch,
mice were treated with ...ablation of GRPR-
diphenylcyclopropenone,
an immunotherapy
expressing neurons
agent that can provoke seems to selectively
sensations of chronic block the sensation
itch in both mice and
humans. B ombesin– of itch...
saporin-treated mice
showed a dramatic loss
of scratching behavior after this treatment.
these findings raise the possi bility that
analogous—and possibly identical—neurons
might be involved in pruritogenic sensory
transduction in humans.
in additional, carefully controlled experi- peppers—provokes sensations of itch, but
ments, the authors showed that the deficits
exhibited by mice treated with bombesin–
saporin were restricted to itch responses.
mice in which GrPr + neurons were
ablated did not exhibit any motor deficits
and, importantly, an exhaustive battery of
pain tests revealed that pain sensitivity was
also not affected. thus, ablation of GrPr-
expressing neurons seems to selectively
block the sensation of itch induced by a
broad range of pruritogenic agents. Genetic
manipulation of GrPr that prevented bom-
besin from binding to the receptor but left
the neuron intact only marginally reduced
itching behavior in response to a variety of
pruritogenic agents. these results indicate
that GrPr-expressing neurons perform
an important role in itch transmission, but
GrPr itself does not. this receptor might,
therefore, merely identify neurons involved
in pruritogenic sensory transduction.
the fact that we are only now starting to
gain an understanding of the central process-
ing of itch highlights the complexity of this
sensory transduction system. as long ago
as 1922, max von Frey, physiologist and
father of the specificity theory of sensa-
tion, regarded itch as a weak form of pain.3
much later, however, histamine was shown
to reliably induce itch, but not pain, when
nature reviews | neurology
© 2009 Macmillan Publishers Limited. All rights reserved
layers of the skin.4 we have since charac-
terized a subgroup of mechano-insensitive
C-fibers in human skin that were strongly
excited by histamine and seemed to provide
the peripheral part of a ‘labeled line’ for
histamine-related itch.5
this ‘labeled line for itch’ hypothesis,
however, does not satisfactorily explain
all aspects of itch sensation. For example,
histamine seems to have
only a minor role in many
forms of clinically impor-
tant itch, such as atopic
dermatitis, liver disease
and kidne y dis e as es.
more over, mu cunain, a
protease that covers the
spicules of the cowhage
plant, induces strong
itching responses, but does
not activate histamine-
sensitive C-fibers. instead, this compound
excites mechanoheat- sensitive C-fibers
(polymodal nociceptors) in superficial skin
layers.6 the fact that the archetypal algogen
capsaicin—the pungent ingredient of chilli
only when applied to very localized areas of
the human epidermis, further highlights the
deficiencies of the current ‘labeled line for
itch’ hypothesis to account for all aspects of
itch sensation.7 in light of the results of the
sun et al. study, we must ascertain whether
all sensory fibers that can detect pruritogenic
stimuli relay the information regarding the
itch stimuli to the Cns via connections with
the GrPr+ neurons in the spinal cord.
How can the itch selectivity of the neurons
described by sun et al. be explained? as
alluded to above, a simple explanation
would be that they receive synaptic con-
nections from both histamine-responsive
and histamine-nonresponsive primary
afferent neurons. at present, it is unclear
whether histamine-responsive afferents are
also involved in itch caused by chloroquine,
diphenylcyclopropenone and protease-
activated receptor 2 agonists. mucunain,
however, has been proven to induce itching
through a peripheral and central pathway
distinct from the histamine-responsive
pathways. unfortunately, the pruritogenicity
of mucunain was not tested in the sun et al.
study. therefore, it will be interesting to dis-
cover whether ablation of the GrPr+ neurons
in the spinal cord also prevents itching
evoked by this pruritogenic protease.
news & views
in summary, GrPr + neurons in the
spinal cord could be essential components
in the still broadly unknown central itch
pathway. establishing that GrPr+ neurons
are essential for pruritic agents other than
those included in the sun et al. study to
evoke sensations of itch would support this
hypothesis. Furthermore, understanding
the central processing of itch perception is
not a purely academic pursuit, since chronic
pruritus is a serious medical problem and
the development of new antipruritic drugs
beyond the antihistamines is an urgent
priority. in this respect, the sun et al. study
has provided important new insights into
itch processing and has identified a possible
target for innovative antipruritic therapy. one
must be cautious, however, when extrapo-
lating from these results. an experimental
approach in the pain field involving ablation
of substance P receptor-positive neurons
attenuated thermal nocifensive behavior in
animals,8 but this finding has not yet been
successfully translated into clinical trials.
Department of Physiology & Pathophysiology,
University of Erlangen/Nuremberg, Erlangen,
Germany (H. o. Handwerker). Department
of Anesthesiology Mannheim, University of
Heidelberg, Mannheim, Germany (M. Schmelz).
Correspondence: H. O. Handwerker, Department
of Physiology & Pathophysiology, University of
Erlangen/Nuremberg, Universitaetsstrasse 17,
D‑91054 Erlangen, Germany
handwerker@physiologie1.uni‑erlangen.de
doi:10.1038/nrneurol.2009.191
Competing interests
The authors declare no competing interests.
1. sun, Y. G. et al. Cellular basis of itch sensation.
Science 325, 1531–1534 (2009).
2. Reich, A., stander, s. C. & szepietowski, J. C.
Drug induced pruritus: a review. Acta Derm.
Venereol. 89, 236–244 (2009).
3. von Frey, M. Physiology of itch sensation
[German]. Arch. Neerland. Physiol. 7, 142–145
(1922).
4. Keele, C. A. & Armstrong, D. Substances
Producing Pain and Itch (edward Arnold,
London, 1964).
5. schmelz, M., schmidt, R., Bickel, A.,
Handwerker, H. O. & Torebjörk, H. e. specific
C-receptors for itch in human skin. J. Neurosci.
17, 8003–8008 (1997).
6. namer, B. et al. separate peripheral pathways
for pruritus in man. J. Neurophysiol. 100,
2062–2069 (2008).
7. sikand, P., shimada, s. G., Green, B. G. &
LaMotte, R. H. similar itch and nociceptive
sensations evoked by punctate cutaneous
application of capsaicin, histamine and
cowhage. Pain 144, 66–75 (2009).
8. nichols, M. L. et al. Transmission of chronic
nociception by spinal neurons expressing the
substance P receptor. Science 286,
1558–1561 (1999).
volume 5 | DeCemBer 2009 | 641