Pain, 66 (1996) 105-108
@ 1996 International Associationfor the Study of Pain. All rights reserved0304-3959/96/$15.00
PAIN 3114
Editorial
Windup and central sensitization are not equivalent
Clifford J. Woolf
Department of Anatomy and Developmental Biology, University College Lmabn, Lorabn WCIE 6BT, (UK)
(Received9 October 1995,accepted 14 February 1996)
One of the most exciting developmentsin pain re-
search over the past decade has been the recognition
that activitydependent changes in the excitability of
central neuroneshave a fundamentalrole in the genera-
tion of pain hypersensitivity(Dubner and Ruda 1992;
Coderre et al. 1993;McMahon et al. 1993;Woolf and
Chong 1993).Indeed it is difficultfrom the contempor-
ary wrs~tive to recallan earlierera, not that longago,
where synapticcontacts betweenneurones were assum-
ed to be stable and sensory processing considered to
reflect f~ed patterns of anatomical connections. The
general expectation then was that a defined stimulus
would alwayselicit a predictableresponseand that the
functional topography of neurones, their receptive
fields,would be unvarying.The shift in our viewof the
adult CNS as being rigid and hard-wired to modifiable
and plastic is the consequence of work by many in-
dividuals,but in the somatosensorysystemat least,owes
most to two discoveries;that of windup and receptive
field reorganizationafter detierentation. Both of these
laid the way for the discovery of the phenomenon of
central sensitization.
Windupwasfirst observedby Lome Mendellworking
in Pat Wall’s laboratory at MIT (Mendell and Wall
1965; Mendell 1966). They noticed that when a
peripheralnervewas stimulatedat sufficientintensityto
activateC-fibres,repetition of the freed stimulusat low
frequencies resulted in a progressive build-up in the
amplitude of the response, recorded extracellularlyas
action potential discharge,in cat dorsal horn neurones.
Thisuse-or activitydependent facilitationwas quite un-
expected. Good luck, as Louis Pasteur observed,
favours the prepared mind, but Lome and Pat were
more than just prepared, they also had the wit to give
the phenomenon a simple but highly evocative name
‘windup’.How much more vivid ‘windup’is in encap-
sulating the change in excitabilityof a central neuron
than ‘progressiveresponseincrement’.Windup has been
observedin cat, rat and primate dorsal horn, in the ven-
tral horn, trigeminalnuclei and the thalamus (Mendell
PZI 0304-3959(96)031 14-4
and Wall 1965;Price et al. 1971;Chung et al. 1979;
Woolfand Swett 1984;Woolf and King 1987;Kawakita
et al. 1993)and in animalsas evolutionarydistinct as a
mollusc (Clatworthy and Walters 1993), the turtle
(Russoand Hounsgaard 1994),and humans (Kristensen
et al. 1992;Price et al. 1994).
Windupis very differentfrom another form of synap-
tic plasticity,that of long term potentiation (LTP), in
that it requiresa very lowfrequencyinput to elicitit and
manifestsonlyduring the train of repetitiveinputs. LTP
requiresa brief high frequencyinput and manifestsas a
potentiatedresponseto subsequentinputs for very pro-
longedperiods.Neverthelessit was inevitablethat when
the ZV-methyl-Gaspartic acid (NMDA) receptor for ex-
citatory amino acids was shown to contribute to LTP
(Herron et al. 1986)a similartest was made for windup,
and sure enough, windup was abolished by NMDA-
receptor antagonist pretreatment (Dickenson and
Sullivan1987;Daviesand Lodge 1987).The reason for
this soon becameclear when it becamepossibleto elicit
windupin an isolated spinalcord preparation (Thomp-
son et al. 1990).The very high quality intracellular
recordingspossible in such preparations have enabled
the synapticpotentialsgeneratedby C-fibresto be anal-
ysed.Unlike A(3fibreswhich elicit a fast excitatory po-
tential lasting severalmilliseconds,C-fibres generate a
synapticpotential lasting up to 20 see, a thousand-fold
longer.This has both an NMDA receptor- (Thompson
et al. 1990)and a tachykininreceptor-mediatedcompo-
nent (Nagy et al. 1993),indicating that it is the conse-
quenceboth of excitatoryamino acid and neuropeptide
release.The very long duration of the synaptic poten-
tials means that at low repetition rates, marked tempo-
ral summation will occur, leading to a cumulative
depolarization(Sivilottiet al. 1993).This summation is
not, however, linear, it increases with each successive
input, and, providing the trajectory is steep enough,
generatesa progressiveincreasein action potential dis-
charge or windup (Sivilottiet al. 1993).The non-linear
nhture of the cumulative depolarization reflects the
106
voltage-dependentproperties of the NMDA receptor
(Mayeret al. 1984).At restingmembranepotentials the
NMDA receptor-ionchannel has a Mg2+ion blocking
the flow of ions through the channel. This means that
even if glutamate binds to the receptor no current flow
occurs. The Mgz+ blWk is, hOWeVer, voltage-
dependent.As the membrane depolarizesthe Mg2+ion
is ejectedfrom the channel and Na+ and Ca2+ions can
flow into the cell further depolarizing the membrane,
which will remove Mg2+from additional NMDA ion
channels. NMDA receptor antagonists, therefore,
reduce the slope of the cumulativedepolarization and
thereby reducdeliminate windup (Thompson et al.
1990).Neurokinin receptor antagonists and morphine
also reduce the C-tibre-evokedslow synapticpotential
(Nagy et al. 1994;Sivilottiet al. 1995)and this may at-
tenuate the summation sufllciently to decrease the
voltage-dependent kick-in of the NMDA channel,
preventingwindup. The summation of synaptic poten-
tials or current can be recorded by intracellular recor-
dings or whole cell patch techniques and also
extracellularly by recording compound potentials
generatedin motor neuronesand passivelyconductedin
decrementalfashion along axons in ventral roots, the
ventral root potential (VRP) (Thompsonet al. 1994).It
must be stressed,though, that a cumulativedepolariza-
tion while necessaryfor the developmentof windup is
not sufficientand these terms must not be confused;the
summation of slow synaptic potentials is not windup.
Windup clearly showed that the same stimulus need
not necessarilyalways produce the same response, in-
deed each C-fibre stimuluschanges the dorsal horn in
sucha way that the responseto any giveninput is depen-
dent, within a narrow time frame, on the history of pre-
vious inputs. Pat Wall in his later studies on the effect
of deafferentationtook a different approach to look at
mother form of neural plasticity. He, largely together
with Marshall Dewor,showedhow removingone set of
inputs to neuronesin the spinalcord resultedin the ap-
pearance of novel inputs (Devor and Wall 1981).This
was,he argued the resultof the strengtheningof normal-
ly ineffectivesynapses (Wall 1977).Conceptually the
major impact of this work was the recognition that
receptivefieldpropertieswere not fixedand this has led
directlyto substantialwork indicatingthat alterationsin
receptive fields are an integral part of higher brain
function.
What then is the relationshipbetweenthesetwo seem-
ingly disparate forms of plasticity; windup and
deafferentation-inducedreceptivefieldchange,and cen-
tral sensitization?Central sensitizationis the expression
of an increase in excitabilityof neurones in the spinal
cord (Woolf 1983).This manifestsat the singlecelllevel
as a changein receptivefieldpropertieswith a reduction
in threshold, an increase in responsivenessand spatial
extent and the recruitmentof novel inputs (Cook et al.
1987). Behaviorally it manifests as abnormal or
heightenedsensitivitywith a spread of hypersensitivity
to uninjured sites (secondary hyperalgesia) and the
generationof pain by low threshold A/3mechanorecep-
tors (allodynia)(Torebjork et al. 1992).These changes
are fundamentalto the generation of clinicalpain and
considerableeffort has been devoted to studying the
cellularmechanismsresponsible.A major clue has been
that central sensitizationcould be evoked by electrical
stimulationof C-fibresat the samefrequenciesthat elicit
windup(Walland Woolf 1986;Woolf and Wall 1986a).
Even more remarkablewas the findingthat central sen-
sitizationcould be preventedpreciselyby those receptor
antagonists or drugs that prevent the developmentof
windup: NMDA receptor antagonists (Woolf and
Thompson 1991;Ren et al. 1992;Coderre and Melzack
1992;Ma and Woolf 1995a),neurokinin receptors an-
tagonists (XU et al. 1991;Ma and Woolf 1995b)and
opiates(Woolfand Wall 1986b).The conclusionseemed
inescapable:windupmust be the trigger,the initiator of
central sensitization.How could this possibly be, how
could a brief period of low frequency sensory input
generatea prolongedperiod of excitabilityincrease.The
answer seemsto be the changes that occur during the
summationof synapticpotentials that cause windup. In
addition to generating an incrementingdepolarization
that will progressivelyincrease action potential dis-
charge by reducing the amount of current required to
reach action potential threshold, the cumulative de-
polarizationalso produces a substantial increase in in-
tracellularcalcium(McDermott et al. 1986).This will
occur partly as a result of the unblocking of NMDA
receptor ion channels,allowinga direct calciuminflux,
partly as a result of the activation of voltage-dependent
calciumchannelsand also as a result of the activation
via G-protein coupled neurokinin receptors, which re-
leaseintracellularcalciumstores(Heath et al. 1994).An
elevationof intracellularcalciumlevelswill lead to the
activationof a number of kinases,of which protein kin-
ase (PKC) seemsmost important. PKC feedsback onto
the NMDA receptor phosphorylating it and partially
removingthe Mg2+channelblockade(Chen and Huang
1992).This now meansthat glutamateon bindingto the
NMDA receptor at the restingmembranepotential will
generatean inward current. This increase in glutamate
sensitivityexplainsthe electrophysiologicalchangesthat
occur during central sensitization; previously sub-
thresholdinputs now beginto generatean action poten-
tial dischargealtering receptivefield properties (Woolf
and King 1990)makingthe wholesystemhypersensitive.
Thisexplains,moreover,both why NMDA receptor an-
tagonistscontinueto be activeoncecentral sensitization
is established (Woolf and Thompson 1991; Ma and
Woolf 1995a)and why inhibition of PKC prevents the
developmentof hyperalgesia(Yashpal et al. 1995).An
increasedintracellularcalcium will also directly or in-

directlyactivatea number of other intracellularenzymes
suchas nitricoxidesynthaseor cyclo-oxygenaseexplain-
ing an involvementof both nitric oxideand prostaglan-
dins in central sensitization(Malmbergand Yaksh 1992;
Meller et al. 1992).
The synapticprocessesthat producewindup are suffi-
cient to produce central sensitizationand it is correct,
therefore, to infer that the presenceof windup is likely
to lead to the developmentof central sensitization.The
reverse is not, however, correct, and any assumption
that central sensitizationcannot occur in the absenceof
windup, is simply wrong. Windup can initiate central
sensitizationbecause it produces an elevation of intra-
cellularcalciumnot becauseof the progressiveincrease
in action potentialdischarge.In other words, if intracel-
lular calciumis elevatedwithout any associatedchange
in action potential firing, central sensitizationwill still
occur. Such an elevation in intracellular calcium may
occur in a number of ways. Firstly by a summation of
synaptic potentials at a rate below that necessary to
change the firing pattern of the cell but sufficient to
allow sutlicientcalciumentry into the cell. In this situ-
ation repetitivestimulationwould seem from an extra-
cellular analysis, to evoke a stable response, but
intracellularrecordingswould reveala slowlyrisingcu-
mulative depolarization. There is electrophysiological
evidencefor the production of a heterosynapticfacilita-
tion analogous to central sensitization,in the presence
of cumulativedepolarizationssubthresholdfor windup
(Thompson et al. 1993).Secondly,activation of meta-
botropic receptors, either neuropeptide or excitatory
amino acid, may increaseintracellularcalciumwithout
any direct change in current flow.
Windup only occurs in a very particular and
somewhat artificial situation, in response to a slowly
repeated stimuluswhich synchronouslyactivates many
C-fibres.Central sensitizationis more general,it can be
produced by the asynchronousactivation of skin,joint,
muscleor visceralafferentsdirectlyby chemicalirritants
(Woolfand Wall 1986a)or as a consequenceof inflam-
mation (Woolf and McMahon 1985)neither of which
producea detectablepattern of progressivelyincreasing
action potential discharge.
Windup has been a key milestone in our increased
understandingof sensoryprocessingin the spinal cord.
It is, though, in terms of the mechanismsthat operate to
produce clinical pain hypersensitivity,an epiphenom-
enon. We must resist the temptation, therefore, to con-
sider windup and central sensitization as being
equivalent. While windup may be suftlcient to cause
central sensitizationit is not necessary and, in conse-
quence, the presence or absence of windup cannot be
used on its own as a predictor of prolonged central
excitabilitychanges.
107
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