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 Neuronal Plasticity: Increasing the Gain in Pain
Clifford J. Woolf, et al.
Science 288, 1765 (2000);
DOI: 10.1126/science.288.5472.1765

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REVIEW: NEUROSCIENCE

Neuronal Plasticity: Increasing the Gain in Pain

Clifford J. Woolf1* and Michael W. Salter2

intense or sustained noxious stimuli result in

We describe those sensations that are unpleasant, intense, or distressing as painful. the co-release of neuromodulators (9) as well
Pain is not homogeneous, however, and comprises three categories: physiological, as glutamate, producing slow EPSPs lasting
inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which tens of seconds (Fig. 3B) (10). This provides
is subject to or an expression of neural plasticity—the capacity of neurons to change for temporal summation (11), and the result-
their function, chemical profile, or structure. Here, we develop a conceptual frame- ing cumulative depolarization is boosted by
work for the contribution of plasticity in primary sensory and dorsal horn neurons to additional N-methyl-D-aspartate (NMDA) re-
the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, ceptor current on removal of the Mg2⫹ block-
modulation, and modification, that by increasing gain, elicit pain hypersensitivity. ade of the channels (12). Depolarization also
activates voltage-gated calcium currents trig-
gering plateau potentials mediated by calci-

P
hysiological pain is an essential early is sufficient, by initiation of action poten- um-activated nonselective cation channels

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warning device that alerts us to the pres- tials. The action potentials are conducted to (Fig. 3B) (13). The net effect is a windup of
ence in the environment of damaging the central nervous system (CNS), where action potential discharge.
stimuli. This is the pain we experience in their invasion of central nociceptor termi-
response to a needle prick. All living organ- nals in the spinal cord initiates transmitter Clinical Pain
isms need to be able to react to noxious release. Fast excitatory synaptic transmis- Inflammatory pain is initiated by tissue dam-
stimuli, and a major evolutionary drive for sion in pain pathways is mediated by gluta- age/inflammation and neuropathic pain by
the development of a plastic nervous system mate acting on AMPA (␣-amino-3-hydroxy- nervous system lesions. Both are character-
might have been the acquisition of the capac- 5-methyl-4-isoxazolepropionic acid) and kai- ized by hypersensitivity at the site of damage
ity to detect and remember danger. nate ligand-gated ion channels (Fig. 3A) (4 ). and in adjacent normal tissue. Pain may ap-
Physiological pain is initiated by special- The excitation is focussed by segmental and pear to arise spontaneously, stimuli that would
ized sensory nociceptor fibers innervating pe- descending activation of inhibitory neurons, never normally produce pain begin to do so
ripheral tissues and activated only by noxious most of which co-release glycine and ␥-ami- (allodynia) and noxious stimuli evoke a greater
stimuli. The sensory inflow generated by no- nobutyric acid (GABA) (5). and more prolonged pain (hyperalgesia) (14).
ciceptors activates neurons in the spinal cord Inflammatory pain hypersensitivity usual-
which project to the cortex via a relay in the Activation-Dependent Plasticity ly returns to normal if the disease process
thalamus, eliciting pain. The nociceptor input Activation of nociceptive pathways is subject is controlled. Neuropathic pain persists long
also activates reflex withdrawal, an increase to activity-dependent plasticity, which mani- after the initiating event has healed and is
in arousal as well as emotional, autonomic, fests as a progressive increase in the response an expression of pathological operation of
and neurohumeral responses. of the system to repeated stimuli. the nervous system rather than a reaction to
Activation-dependent plasticity in noci- pathology.
Activation of the Pain System ceptor terminals: Autosensitization. The high The plasticity responsible for clinical pain
Physiological pain (Fig. 1) starts in the pe- threshold of nociceptor terminals can be de- hypersensitivity has two general forms, mod-
ripheral terminals of nociceptors with the ac- creased either by changes in the transducers ulation and modification (Fig. 1). Modulation
tivation of nociceptive transducer receptor/ themselves as a result of prior activation, a represents reversible changes in the excitabil-
ion channel complexes, which generate depo- phenomenon we term autosensitization, or by ity of primary sensory and central neurons
larizing currents in response to noxious stim- an increase in the excitability of the terminal mediated by posttranslational alterations in-
uli (Fig. 2). Transducer proteins that respond membrane, which we call heterosensitization, duced in receptors/ion channels by activation
to extrinsic or intrinsic irritant chemical stim- that is initiated by sensitizing stimuli that do of intracellular signal transduction cascades.
uli (VR1, DRASIC, P2X3) are selectively not activate the transducers. Modification represents long-lasting alter-
expressed in sensory neurons (1). Noxious Autosensitization of vanilloid receptors ations in the expression of transmitters/recep-
heat transducers include the vanilloid recep- upon their repeated activation by heat, cap- tors/ion channels or in the structure, connec-
tors VR1 and VRL1 (2). A transducer for saicin, or protons is observed electrophysi- tivity and survival of neurons, such that the
noxious mechanical stimuli has not been ologically (6) and parallels changes in heat system is grossly modified, distorting its nor-
identified, although studies in Caenorhabdi- responsive nociceptors and pain in humans mal stimulus-response characteristics.
tis elegans suggest that it may belong to the (7). The changes are rapid in onset, substan-
mDeg ion channel family (3). tial, and readily reversible, and may represent Modulation of the Pain System
Transduction is followed, if the current conformational changes in the protein in- The major mechanism responsible for modu-
duced by heat, or alterations secondary to lation is phosphorylation of receptor/ion chan-
1
Neural Plasticity Research Group, Department of calcium entry through the transducer (8). nels, or associated regulatory proteins, altering
Anesthesia and Critical Care, Massachusetts General Activation-dependent plasticity in dorsal intrinsic functional properties or cell-surface
Hospital and Harvard Medical School, MGH-East, horn neurons: Windup. Low-frequency acti- expression of channels in primary sensory and
Charlestown, MA 02129, USA. 2Program in Brain and
Behaviour, Hospital for Sick Children and University
vation of nociceptors by mild noxious stimuli dorsal horn neurons. The intracellular pathways
of Toronto Centre for the Study of Pain, Toronto, generates fast excitatory postsynaptic poten- involve interactions of serine/threonine and
Ontario M5G 1X8, Canada. tials (EPSPs) that signal the onset, duration, tyrosine kinase signaling cascades.
*To whom correspondence should be addressed. E- intensity, and location of the stimulus (Fig. Modulation of the peripheral terminals of
mail: [email protected] 3A). Higher frequency inputs generated by nociceptors: Heterosensitization. An increase

www.sciencemag.org SCIENCE VOL 288 9 JUNE 2000 1765

 SCIENCE’S COMPASS
in the excitability of the nociceptor terminal es and depressed inhibition, thereby amplify- regulated AMPA channel insertion dependent
membrane will reduce the amount of depo- ing responses to noxious and innocuous upon PKC has been demonstrated (37). Thus,
larization required to initiate an action poten- inputs. The changes may be restricted to the homosynaptic potentiation in the dorsal horn
tial discharge. This modulation occurs on activated synapse (homosynaptic) or spread is likely to proceed via mechanisms analo-
exposure of the terminal to sensitizing agents to adjacent synapses (heterosynaptic). Most gous to LTP in CA1. However, given that
and contributes to peripheral sensitization. excitatory input to pain pathway neurons is expression of CaMKII is low in the dorsal
The sensitizing agents include inflammatory subthreshold, and increased gain results in horn, another calcium-dependent serine/thre-
mediators (PGE2, 5-HT, bradykinin, epi- recruitment of these inputs to the output of onine kinase, such as PKC, may play an
nephrine, adenosine) and neurotrophic fac- the neurons, causing them to fire to normally equivalent role.
tors (NGFs) released during tissue damage or ineffective inputs (28, 29). These changes con- Because nociceptors do not usually fire at
by inflammatory cells that may or may not stitute central sensitization and are responsi- high frequencies, homosynaptic potentiation
activate the terminal, but which also sensitize ble for pain produced by low-threshold affer- may be limited to very intense stimuli. Het-
it to subsequent stimuli (15, 16 ). The modu- ent inputs and the spread of hypersensitivity erosynaptic potentiation, because it can be
lation is the result of the parallel activation of to regions beyond injured tissue (30, 31). initiated by low-frequency nociceptor inputs
intracellular kinases by G protein coupled– Activity-dependent enhancement of trans- (1.0 Hz), is a more prominent feature of
and tyrosine kinase membrane-bound recep- mission is common at excitatory synapses synaptic modulation in the dorsal horn, en-
tors (17 ) activating protein kinase A (18) or throughout the CNS and is broadly separable hancing synapses not activated by the condi-
protein kinase C ε (19, 20), phosphorylating a into NMDA receptor– dependent and NMDA tioning input, evoking dispersed hypersensi-
tetrodotoxin (TTX) resistant sensory neuron– receptor–independent types. Homosynaptic tivity as revealed by increases in receptive

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specific sodium ion channel SNS and possi- potentiation of AMPA-receptor responses at field size and recruitment of novel inputs (38,
bly VR1 (21). Phosphorylation of SNS alters synapses on dorsal horn neurons is produced 39). Whenever C-fiber nociceptors are acti-
its properties, including activation threshold experimentally by brief duration, high-fre- vated more than transiently, they induce cen-
and rate of activation/inactivation, and in- quency (100 Hz) nociceptor stimulation and tral sensitization and this NMDA receptor–
creases the magnitude of the sodium current is dependent upon NMDA receptor activation mediated phenomenon is a major component
to depolarization (22, 23). SNS knockdown (32). The requirement for high-frequency af- of inflammatory and neuropathic pain (40,
and knockout (24, 25) indicate that it contrib- ferent input and NMDA receptors is like that 41). Involvement of NMDA receptors is at-
utes to inflammatory pain hypersensitivity. of long-term potentiation (LTP) in CA1 hip- tributable to two mechanisms (Fig. 3C). First,
Because different sensitizing signal mole- pocampal neurons (33). At CA1 synapses, a cumulative depolarization produced by
cules acting on different receptors effect the LTP is initiated by a signaling cascade in- summation of nociceptor-evoked slow synap-
same end result, inhibiting a single sensitiz- volving enhancement of NMDA receptor tic potentials (42) leading to suppression of
ing agent is unlikely to completely eliminate function by the tyrosine kinase Src, raised Mg2⫹ blockade of NMDA channels. Second,
peripheral sensitization. intracellular [Ca2⫹], activation of calcium/ enhanced NMDA channel gating through
Modulation of nociceptive synaptic trans- calmodulin-dependent kinase II (CaMKII) convergent signaling cascades from G pro-
mission: Central sensitization. Modulation in and PKC, and enhanced AMPA channel con- tein–coupled receptors (43), such as NK1,
central pain pathways is triggered by periph- ductance and/or cell-surface expression (34, EP, or mGlu receptors, and receptor tyrosine
eral nociceptor input and results in enhanced 35). In dorsal horn neurons, NMDA receptors kinases, such as the trkB receptor, all of
responsiveness of pain transmission neurons, are known to be up-regulated by Src (36 ) and which are present in the superficial dorsal
which either outlasts the initiating input or
requires a low-level peripheral drive to main-
tain it (26, 27). Modulation involves activa-
tion of intracellular signaling cascades lead-
ing to facilitated excitatory synaptic respons-

Fig. 1. The three forms of neural plasticity that

increase gain in the somatosensory system to
produce pain hypersensitivity are illustrated,
highlighting changes they produce and their Fig. 2. Neural plasticity in primary sensory neurons. Activation, modulation, and modification all
effects on pain transmission. alter the nociceptor peripheral terminal threshold.

1766 9 JUNE 2000 VOL 288 SCIENCE www.sciencemag.org

 SCIENCE’S COMPASS
horn where nociceptors terminate (44 ). A tors lacking the edited form of the GluR2 ment, but have a role in the maintenance of
likely point of convergence for G protein– subunit. These AMPA receptors allow calci- neuronal phenotype in the adult (49). In-
coupled receptor and receptor tyrosine kinase um influx sufficient to produce lasting facil- creases in these signal molecules, which
signaling in the pathway to enhanced NMDA itation of synaptic transmission in dorsal horn occur after inflammation, and decreases af-
receptor function is PKC, which has been neurons (47). ter loss of contact with the target after
shown in hippocampal neurons to potentiate Long-lasting depression of inhibition: peripheral axon damage, initiate marked
NMDA currents indirectly through activating Disinhibition. Also important for central alterations in the expression of transmitters,
Src (43). sensitization is depression of spinal inhib- synaptic neuromodulators, ion channels, G
Another kinase signaling cascade in- itory mechanisms. Long-term depression of protein–coupled receptors, and growth-associ-
volved in synaptic plasticity is the mitogen- transmission at primary afferent synapses ated and structural proteins. Apart from ret-
activated protein kinase pathway (33). In the onto substantia gelatinosa neurons, many of rograde signals, electrical activity alone, due
superficial dorsal horn, MAPK phosphoryl- which are GABA/glycinergic, can be elic- to calcium influx through voltage-gated ion
ation increases following nociceptive stimu- ited by activation of A␦ primary afferents channels, can change transcription in sensory
lation and inhibiting it suppresses the second (48). The depression, which requires neurons (44).
phase of the formalin test (45), which has NMDA receptor activation and a postsyn- After inflammation, there is an up-reg-
been thought, because of its selective sensi- aptic calcium increase, is likely to be mech- ulation of VR1 and SNS (50, 51), which,
tivity to intrathecal NMDA receptor antago- anistically similar to LTD in other brain when transported to the peripheral terminal,
nists, (46 ) to be indicative of a suppression of regions. may increase sensitivity to inflammatory
central sensitization. mediators and susceptibility to peripheral
Modification of the Pain System

Downloaded from www.sciencemag.org on April 8, 2009

NMDA receptor-independent mecha- sensitization. Increases in substance P and
nisms for facilitating excitatory synaptic Modification of primary sensory neurons. brain-derived neurotrophic factor (BDNF),
transmission are also potentially important in Target-derived growth factors retrogradely two synaptic neuromodulators, also alter
the pain system. In particular, subpopulations transported from the target to the cell body the central drive evoked in the dorsal horn
of dorsal horn neurons express AMPA recep- are essential for survival during develop- by nociceptors (52–54 ).

Fig. 3. Modes of neural plasticity at synapses onto nociceptive transmission duces central sensitization through facilitating AMPA/kainate and NMDA
neurons in the dorsal horn of the spinal cord. The neurons are activated by receptor function or cell-surface expression. Modification is mediated by
fast EPSPs and enhanced by slow EPSPs, plateau potentials, and windup. induced expression of gene products, loss of inhibitory interneurons, and
Modulation through intracellular kinase/phosphatase signaling cascades pro- establishment of aberrant excitatory synaptic connections.

www.sciencemag.org SCIENCE VOL 288 9 JUNE 2000 1767

 SCIENCE’S COMPASS
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