You are on page 1of 11

European Neuropsychopharmacology (2012) 22, 81–91

www.elsevier.com/locate/euroneuro

REVIEW

Mechanisms of neuropathic pain


Florian T. Nickel, Frank Seifert, Stefan Lanz, Christian Maihöfner ⁎

Department of Neurology, University of Erlangen-Nuremberg, Germany

Received 8 November 2010; received in revised form 12 April 2011; accepted 14 May 2011

KEYWORDS Abstract
Neuropathic pain;
Pathophysiology; Neuropathic pain is a disease of global burden. Its symptoms include spontaneous and stimulus-
Sensitization; evoked painful sensations. Several maladaptive mechanisms underlying these symptoms have
Reorganization; been elucidated in recent years: peripheral sensitization of nociception, abnormal excitability of
Sympathetically afferent neurons, central sensitization comprising pronociceptive facilitation, disinhibition of
maintained; nociception and central reorganization processes, and sympathetically maintained pain. This
Symptoms review aims to illustrate these pathophysiological principles, focussing on molecular and
neurophysiological findings. Finally therapeutic options based on these findings are discussed.
© 2011 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction
Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazelo-
Nociceptive pain is a basic and essential function of the
proprionic acid; ASIC, acid sensing ion channel; CGRP, calcitonin
peripheral and central nervous system. It has a warning
gene-related peptide; CIP, congenital insensitivity to pain; CRPS,
complex regional pain syndrome; DRG, dorsal root ganglion; HPC-
function and signalizes imminent or actual tissue damage. As
nociceptors, nociceptors sensitive to heat, pinch and cold; LPA, such nociceptive pain preserves body integrity. This is
lysophosphatidic acid; LTP, long-term potentiation; MAPK, mitogen- illustrated by diseases with congenitally decreased pain
activated protein kinase; mGluR, metabotropic G-protein coupled sensitivity (Manfredi et al. 1981). Nonsense mutations of the
glutamate receptor; NaV, voltage-gated sodium channel; NGF, nerve SCN9A gene for instance cause a congenital insensitivity to
growth factor; NMDA, N-methyl-D-aspartate; PAG, periaqueductal pain (CIP) (Cox et al. 2006). SCN9A encodes the alpha-
grey; PEPD, paroxysmal extreme pain disorder; QST, quantitative subunit of the voltage-gated sodium channel NaV1.7. The loss
sensory testing; RVM, rostral ventral medulla; SCS, spinal cord of function of this channel predisposes to injuries and
stimulation; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
mutilations in early childhood and a reduced life expectancy.
antidepressant; TENS, transcutaneous electrical nerve stimulation;
Neuropathic pain on the other hand is a pain arising as a
TRP, transient receptor potential-channel; TTX, tetrodotoxin.
⁎ Corresponding author at: Department of Neurology, University of
direct consequence of a lesion or disease affecting the
Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. somatosensory system (Treede et al. 2008). Function is
Tel.: +49 9131 8533001; fax: +49 9131 8536597. altered at different levels of the peripheral and central
E-mail address: christian.maihoefner@uk-erlangen.de nervous system. It is in\creasingly recognized that specific
(C. Maihöfner). symptoms and signs correlate with involved structures and

0924-977X/$ - see front matter © 2011 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2011.05.005
82 F.T. Nickel et al.

pathomechanisms (Scholz et al. 2009; Woolf and Decosterd horn, disinhibition of nociception at the spinal inhibitory
1999). Knowledge of these is essential for guiding patho- network, sympathetically maintained pain, and CNS
physiology-based rather than etiology-based treatment. reorganization processes (Fig. 1). These items represent
Neuropathic pain is a disease of global burden. The a merely conceptual framework, but significant overlap
prevalence of chronic neuropathic pain lasting for more than does occur. They do not exclude but complement each
3 months has been reported in a French survey at about 6.9% other.
(Bouhassira 2008), with middle-aged people (50–64 years)
being the most frequently affected. Chronic neuropathic
pain seems to have significantly greater pain intensity and 2. Sensitization of nociceptors
duration than other types of pain (Torrance et al. 2006). In an
observational study the employment status of 42.9% was In nociceptive and neuropathic pain sensitization of noci-
affected, with an average of 5.5 days missed from work in ceptors is an important mechanism. It contributes to
the four weeks prior to the study (McDermott et al. 2006). conditions like acute herpes zoster, postherpetic neuralgia,
Diabetic polyneuropathy and neuropathies associated with and complex regional pain syndrome. These are prime
chronic low back pain are considered the most frequent examples for the coexistence of different mechanisms in
causes of neuropathic pain. As nociceptive and neuropathic neuropathic pain syndromes. Nociceptors are receptors with
pains often are not well-defined in low back pain there is stimulus-specific different modalities located at the free
increasing agreement to use the term “mixed pain” nerve endings of unmyelinated C fibers and lightly myelin-
(Freynhagen et al. 2008). In many of these patients ated Aδ fibers (Julius and Basbaum 2001). They are activated
nociceptive pain originating from muscles, capsules, liga- by noxious mechanical, thermal, and chemical stimuli and
ments and C fibers sprouting into intervertebral discs and modulated by a variety of endogenous peptides like
neuropathic pain due to radicular compression and inflam- bradykinin, substance P and calcitonin gene-related peptide
matory activation of C fibers are combined (Freynhagen and (CGRP). Mechanosensitive nociceptors are activated specif-
Baron 2009). ically by pressure and mechanical stress. Mechano-heat
sensitive nociceptors additionally detect heat above a
1.1. Symptoms of neuropathic pain threshold of 43–45 °C. Most nociceptors are polymodal and
are linked to C fibers. So called “silent” nociceptors
represent a distinct class of nociceptors. In microneuro-
Typically negative and positive sensory symptoms coexist
graphic experiments theses nociceptors were shown to
in neuropathic pain. Negative symptoms include deficits
display a high activation threshold (Schmidt et al. 1995).
of different somatosensory qualities such as tactile
Only after lowering the activation threshold, by different
hypoesthesia or anesthesia, thermal hypoesthesia, pin-
substances via different receptors, does this subpopulation
prick hypoalgesia, and loss of vibratory sensation. These
of C fibers convert a noxious stimulus into a membrane
symptoms are uncomfortable but not painful. Spontaneous
depolarisation and action potentials.
positive sensations like paresthesia and dysesthesia,
The nociceptors are activated either by exogenous or
paroxysmal pain, and ongoing superficial pain also occur.
endogenous substances. The latter comprises inflammatory
Other positive symptoms are stimulus-evoked and include
mediators (bradykinin, prostaglandins and other derivates of
hyperalgesia and allodynia. In mechanical hyperalgesia
arachidonic acid), neurotransmitters (excitatory amino
normally slightly painful pinprick stimulation is perceived
acids, neurokinins, serotonin, noradrenalin, histamine),
as more painful. Mechanical dynamic and mechanical
and growth factors (nerve growth factor, NGF) (Julius and
static allodynia describe a state in which pain is evoked
Basbaum 2001). Lipid metabolites like lysophosphatidic acid
by light moving touch or light pressure, respectively.
(LPA) also play a role in neuropathic pain (Ueda 2008). LPA is
Accordingly cold and heat allodynia is evoked by normally
released after tissue injury and acts via G-protein coupled
non-painful cold and warm stimuli. To evaluate these
LPA receptors. LPA1 receptor deficient mice do not develop
negative and positive symptoms quantitative sensory
neuropathic pain like their wild-type littermates, whereas
testing (QST) could be performed (Hansson et al. 2007;
intrathecal LPA injection leads to typical neuropathic
Yarnitsky 1997). A standardized protocol with age-
changes, both clinically and biochemically (Inoue et al.
matched reference values was established in 2006 (Rolke
2004).
et al. 2006).
After axonal damage of a peripheral nerve Wallerian
These signs and symptoms with their underlying mecha-
degeneration occurs. The axon and the myelin sheath are
nisms are not specific to their etiology. Efforts are made to
degraded, and macrophages as well as other types of immune
correlate clinical and QST data with pathophysiological
cells (neutrophils, T cells) infiltrate (Moalem and Tracey
mechanisms to provide a base for future treatment trials.
2006; Scholz and Woolf 2007). Proinflammatory cytokines
(interleukins, tumor necrosis factor α) and inflammatory
1.2. Mechanisms of neuropathic pain mediators (bradykinin, prostaglandins) as well as growth
factors (nerve growth factor, NGF) are released. These
In the last years several mechanisms perpetuating neuro- changes promote hyperalgesia and allodynia (Sommer and
pathic pain have been elucidated. In this review we focus Kress 2004). For example after partial peripheral nerve
on six classes of maladaptive changes in the peripheral, lesion the development of hyperalgesia is associated with
central and autonomic nervous system: sensitization of increased NGF levels (Pezet and McMahon 2006). The
nociceptors, abnormal ectopic excitability of affected application of Anti-NGF antibodies attenuated the develop-
neurons, pronociceptive facilitation at the spinal dorsal ment of hyperalgesia in a rat ischiadic nerve constriction
Mechanisms of neuropathic pain 83

Figure 1 Synopsis of molecular mechanisms contributing to neuropathic pain (see text for details). (A) Sensitization of the
nociceptor. (B) Abnormal ectopic excitability of afferent neurons and sympathetically maintained pain. (C) Disinhibition of
nociception at the spinal inhibitory network. (D) Pronociceptive facilitation at the spinal dorsal horn.

model (Ro et al. 1999). Examples for neuropathic pain kinase, MAPK), and nitric oxide signaling pathways account
syndromes with a significant inflammatory component are for functional and structural changes perpetuating pain
complex regional pain syndrome (CRPS) and postherpetic experience (Hucho and Levine 2007). For instance bradykinin
neuralgia. and prostaglandin E2 activate protein kinase A and C.
Amongst others sensitization of nociceptors is mediated Consequently TPRV1 function is potentiated (Julius and
by the transient receptor potential (TRP) family of non- Basbaum 2001). Additionally the expression of TRPV1
specific cation channels. A prominent member is TRP channels is upregulated in models of neuropathic pain
vanilloid 1 (TRPV1). It is activated by heat and capsaicin (Hong and Wiley 2005; Hudson et al. 2001).
and highly expressed in Aδ and C fibers (Lumpkin and Currently available pharmacologic agents target arachi-
Caterina 2007). TRPV1 activation thus evokes a burning pain. donic acid metabolism (cyclooxygygenase inhibitors, gluco-
TRPV1 channels are also opened by strong acid stimuli, corticoids) and TRPV1 channels (capsaicin). Capsaicin is a
whereas acid-sensing ion (ASIC) channels are activated by TRPV1 agonist. After a period of increased burning sensation
moderately acidic pH (Lingueglia 2007). topical capsaicin leads to a reversible loss of function in the
Furthermore, in neuropathic pain intracellular signaling is nociceptive afferents.
altered. Second messengers (like cyclic AMP, cAMP), protein The role of other TRP ion channels expressed in
kinases (protein kinase A and B, mitogen-activated protein nociceptors – especially TRPA1, an irritant-activated ion
84 F.T. Nickel et al.

channel, and TRPM8, an cold-activated ion channel – in the There is a considerable body of evidence that drugs with
pathophysiology of neuropathic pain remains controversial sodium channel blocking properties are effective in treating
(Xing et al. 2007; Zurborg et al. 2007). neuropathic pain. These include carbamazepin, oxcarbaze-
pin, phenytoin and lidocain (Gilron et al. 2006). Lamotrigin
might be beneficial in neuropathic pain due to HIV infection
3. Abnormal ectopic excitability of afferent (Simpson et al. 2003), stroke (Vestergaard et al. 2001), and
neurons diabetic neuropathy (Eisenberg et al. 2001). But significant
evidence supporting its widespread use is lacking according
In neuropathic pain syndromes abnormal ectopic excitability to a Cochrane Database review (Wiffen and Rees 2007).
of afferent neurons leads to positive symptoms. Paraesthe- Tricyclic antidepressants (TCAs) also block sodium channels
sias and dysaesthesias are caused by spontaneous discharge beyond other modes of action. This property contributes to
of myelinated Aβ fibers. In thinly or unmyelinated Aδ and C their analgesic effect. Different TCAs inhibited NaV1.7 at
fibers altered excitability results in lancinating and burning therapeutic plasma concentrations (Dick et al. 2007),
pain. Apparently these symptoms are generated by sodium whereas selective serotonin reuptake inhibitors (SSRIs) did
channels, which are differentially expressed and distributed not. This might explain why SSRIs are less effective in
and abnormally active in neuropathic pain (Amir et al. 1999; treating neuropathic pain. Not surprisingly, type I antiar-
Tal et al. 1999). Sensory neurons contain two groups of rhythmics like lidocaine and mexiletine were shown to exert
voltage-gated sodium channels: fast acting tetrodotoxin- analgesic effects in neuropathic pain. The therapeutic
sensitive (TTX-S) and slowly acting tetrodotoxin-resistant benefit was equal to morphine, gabapentin or amitriptyline
(TTX-R) channels. The latter are detected only in nociceptor (Jarvis and Coukell 1998; Tremont-Lukats et al. 2005) with no
sensory neurons and are considered to be involved in difference in side effects. In neuropathic pain models,
pathological pain states (Cummins et al. 2007). After nerve sodium blockade had pre-emptive effects on the develop-
injury the concentration of sodium channels of either type ment of hyperalgesia (Abram and Yaksh 1994; Koppert et al.
rises at the site of the lesion and in the whole axon (Woolf 2001).
and Mannion 1999). Nine subtypes of voltage-gated sodium Also topiramate might reduce neuropathic pain, as shown
channels (NaV1.1 to NaV1.9) have been identified so far. in painful diabetic neuropathy (Raskin et al. 2004; Thienel et
NaV1.7, NaV1.8 and NaV1.9 seem to be particularly involved al. 2004). Pharmacodynamically, topiramate blocks voltage-
in pain perception. As mentioned above, nonsense-mutations dependent sodium channels, influences GABA-mediated
of the SCN9A gene, coding for the α subunit of NaV1.7 and chloride current increment and glutamate-mediated neuro-
impairing its function, result in a congenital insensitivity to transmission inhibition, and also attenuates calcium (Ca 2+)
pain (Cox et al. 2006). In contrast, different activating point influx at the site of voltage-gated Ca 2+ channels (Guerrini
mutations lead to the autosomal-dominantly inherited and Parmeggiani 2006). After neuronal damage these Ca 2+
erythromelalgia, a disease with severe burning pain and channels are expressed at a high level (Luo et al. 2001;
skin redness (Han et al. 2006; Yang et al. 2004). Also the Matthews and Dickenson 2001), indicating a sensitization.
paroxysmal extreme pain disorder (PEPD), characterized by Activation of voltage-gated Ca 2+ channels leads to the
episodes of burning pain in the rectal, ocular and mandibular release of substance P and glutamate (White et al. 1989).
areas, was linked to several missense-mutations of the The expression level of the α2δ subunit of voltage-gated Ca 2+
SCN9A gene (Fertleman et al. 2006). In a rat model of painful channels in dorsal root ganglia correlates with the develop-
diabetic neuropathy small dorsal root ganglion (DRG) neurons ment of allodynia (Luo et al. 2001). Gabapentin and
displayed elevated NaV1.7 immunoblot reactivity. Sodium pregabalin inhibit this subunit, thereby reducing neuropathic
currents increased significantly in these neurons (Hong et al. pain (Gilron 2007). Intrathecally applied ziconotide may also
2004). The pronociceptive role of Nav1.8 could be shown in be effective (Rauck et al. 2006), as it blocks Ca 2+ channels
some inflammatory and neuropathic pain states (Jarvis et al. located in the superficial laminae of the dorsal column.
2007) as well as in cold-induced pain (Zimmermann et al.
2007). NaV1.9 seems to play a role in setting membrane
resting potential by generating a persistent sodium current 4. Pronociceptive facilitation at the spinal
(Wood et al. 2004). dorsal horn
In phantom limb pain, changes in sodium channel
expression and function are considered to contribute to Whereas the above mentioned mechanisms typically lead to
painful paraesthesias and lancinating pain. These symptoms spontaneous painful sensations, pin-prick hyperalgesia, cold
result in part from the spontaneous discharges of Aδ and C hyperalgesia and dynamic allodynia are clinical signs related
fibers due to increased sodium channel expression, mainly to central sensitization (Woolf and Mannion 1999). Primary
Nav1.7 (Bird et al. 2007) and Nav1.8 (Roza et al. 2003). afferent nociceptive Aδ and C fibers terminate at two types
Another cause are pathological connections of axons, so of spinal dorsal column neurons: spinal projection neurons
called ephapses, leading to “short-circuit excitation” of and interneurons. Spinal projection neurons innervate higher
nociceptive neurons (Flor et al. 2006). The idea of novel neuronal centres including the thalamus and the parabra-
sodium channel blockers selectively inhibiting the action of chial area. Interneurons serve a wide variety of functions.
Nav1.7 and 1.8 is appealing (Rogers et al. 2006). CDA54 is a For instance, they provide polysynaptic connections from
substance inhibiting Nav1.7 and 1.8 without penetrating into low threshold primary afferents to lamina I projection
the central nervous system. In two animal models it was neurons and modify synaptic transmission at the spinal
shown to reduce neuropathic pain. Cardiac conduction level. The intermediolateral cell column and spinal motor
abnormalities were not detected (Brochu et al. 2006). areas are also indirectly connected to nociceptive input.
Mechanisms of neuropathic pain 85

Glutamate is the major excitatory transmitter in the variety of diffusible mediators including pro- inflammatory
central nervous system including the pain system. There are cytokines and chemokines that induce hyperexcitibility in
three types of glutamate receptors involved in the transmis- dorsal horn neurons, thus contributing to pathologically
sion of peripheral pain signals: the two ionotropic receptors, enhanced pain signaling (Inoue et al. 2004). There is also
the α-amino-3-hydroxyl-5-methyl-4-isoxazeloproprionic acid evidence that spinal astrocytes play a role in the mainte-
(AMPA) receptor and the N-methyl-D-aspartate (NMDA) nance phase of neuropathic pain (Kawasaki et al. 2008).
receptor, and the metabotropic G-protein coupled gluta-
mate (mGluR) receptors. AMPA receptor activation of dorsal
horn neurons mediates the basic response to acute painful 5. Disinhibition of nociception at the spinal
stimuli. NMDA receptors are physiologically blocked by a inhibitory network
magnesium ion. This block is likely removed by repetitive
depolarization resulting in an amplification and prolongation An important phenomenon caused by disinhibition at the
of the noxious input in the spinal dorsal horn (D'Mello and spinal level is the thermal grill illusion, first described by the
Dickenson 2008). Calcitonin-gene related peptide (CGRP) Danish physiologist Thunberg in 1896. It is a nice example of
and substance P, which are found in C fiber terminals as well, pain not related to nociceptor activation. In the thermal grill
may also contribute to this disinhibition of NMDA receptors illusion non-painful cold stimulation is perceived as painful
(Khasabov et al. 2002; Suzuki et al. 2003). This activity- heat. This paradoxical pain was attributed to disinhibition of
dependent sensitization results in the long-term potentia- peripheral and central noxious heat responsive pathways
tion (LTP) of noxious stimuli. (Craig and Bushnell 1994). In the periphery paradoxical heat
There are three classes of metabotropic glutamate pain is transmitted by C fibers, as electrophysiological
receptors. Receptors of group I (mGluR1 and 5) activate experiments could show (Susser et al. 1999). Under normal
phospholipase C, thereby enhancing synaptic transmission circumstances cold-activated Aδ fibers contribute to the
and neuronal discharge. In contrast, group II (mGluR2 and 3) inhibition of polymodal C nociceptors. Physiologically the
and III (mGluR 4, 6, 7 and 8) receptors inhibit the adenylyl input of these C nociceptors, which are sensitive to heat,
cyclase and reduce transmission of nociceptive signals (Pan pinch, and cold (HPC nociceptors), in the lamina I of the
et al. 2008). Accordingly, mGluR1-antagonists and antibodies spinal dorsal horn is masked by Aδ thermoceptors. After
have been shown to reduce neuropathic pain in animal inhibition of the Aδ input, for example by concomitant warm
models (Fundytus et al. 1998; Wu et al. 2007). As a response sensation in the thermal grill experiment or a by a peripheral
to ongoing nociceptive input intracellular signaling cascades neuropathy affecting Aδ fibers, HPC nociceptor signaling is
are altered. Activation of protein kinase C, the mitogen- disinhibited (Craig 2002).
activated protein kinase (MAPK) pathway, nitric oxide The activity of the dorsal horn neurons projecting into
synthetase, and others may induce synaptic plasticity like central structures plays a pivotal role in pain perception. It is
long term potentiation (LTP) (D'Mello and Dickenson 2008; subjected to a couple of inhibitory factors. Descending
Woolf and Salter 2000). inhibitory serotonergic, noradrenergic and dopaminergic
These adaptive mechanisms result in increased excitabil- pathways originate from the periaqueductal gray (PAG),
ity of nociceptive central neurons, which then become locus coeruleus, the raphe nuclei, and the rostral ventral
activated not only by low level stimulation of C and Aδ fibers medulla (RVM). Opioid receptors are highly expressed. At the
but also by Aβ fibers. This is reflected in extended receptive spinal dorsal horn GABAergic and glycinergic synapses exert
fields of nociceptive fibers in the periphery and increased inhibitory effects. Activation of GABAA receptors via the α2
stimulus-evoked painful sensations like pin-prick hyperalge- or α3 subunit alleviates pain in inflammatory and neuro-
sia and mechanical-dynamic allodynia. pathic pain mouse models (Knabl et al. 2008).
Thus, the idea of blocking NMDA receptors to manage Some data from animal models demonstrated a reduced
neuropathic pain is appealing; however, clinical trials with activity and efficacy of descending inhibitory pathways and
the NMDA receptor antagonists dextromethorphan and of the endogenous endorphin system. For example, the drop
memantine yielded equivocal results (Rice and Hill 2006). in discharge frequency, normally brought on by the admin-
Ketamine on the other hand seems to be effective in istration of morphine, was partially lost after deafferenta-
neuropathic pain syndromes like post-herpetic neuralgia tion by dorsal rhizotomy (Zimmermann 2001). Inhibitory
and complex regional pain syndrome (CRPS) (Eide et al. 1994; synaptic transmission by GABA and glycine has been shown to
Kiefer et al. 2008). drop in chronic neuropathic pain (Zeilhofer 2008). Conse-
Recent findings revealed an active involvement of spinal quently, these changes account for a disinhibition of
glial cells in the pathogenesis of nerve injury induced nociceptive input and an increase in pain sensitivity. Also
neuropathic pain (Inoue et al. 2004; Tsuda et al. 2005). increased spinal release of dynorphin, an endogenous opioid
After peripheral nerve injury spinal microglia cells, the peptide, contributes to neuropathic pain after peripheral
immune cells of the CNS, are converted from a resting state nerve lesion and correlates to thermal hyperalgesia (Malan et
to an activated state by means of a set of phenotypic and al. 2000; Ossipov et al. 2000). Intrathecal dynorphin exerts
functional changes. Injured peripheral nerve endings and only minor antinociceptive but major excitatory effects on
affected dorsal horn neurons signal to spinal microglia cells pain transmission (Vanderah et al. 2000). Blockade of
via purinergic receptors, chemokines and chemokine re- dynorphin restores analgesic properties of morphine after
ceptors as well as immune-related molecules (lipopolysac- spinal nerve lesion (Ossipov et al. 2000). The mechanism of
charides, toll-like receptors) (Guo and Schluesener 2007; dynorphin-induced hyperalgesia remains unclear. Expression
Inoue et al. 2004), which leads to protein kinase (p38 MAPK) of dynorphin in inhibitory interneurons may reduce their
activation (Inoue et al. 2004). Activated microglia release a activity (Costigan and Woolf 2002). Recently, dynorphin was
86 F.T. Nickel et al.

shown to act on bradykinin receptors at the spinal dorsal underwent sympathectomy, electrical stimulation of the
horn. The pronociceptive effect of intrathecal administra- sympathetic trunk resulted in pain recurrence and hyper-
tion of dynorphin A was blocked by antagonists for the algesia. Structural evidence for increased coupling of
bradykinin receptors (Lai et al. 2006). sympathetic fibers to DRG neurons after peripheral nerve
Recently, patients with complex regional pain syndrome injury comes from histological studies showing sympathetic
(CRPS), a neuropathic pain condition after limb trauma, sprouting into DRGs (Shinder et al. 1999). However, the
were shown to display differential activity in endogenous functional relevance of this sympathetic basket formation
pain modulatory systems (Seifert et al. 2009). The adaption remains unclear (Ramer et al. 1999). Finally, in CRPS
to painful electrical stimuli was decreased in the affected sympathetic vasoconstrictor activity produced by whole-
and unaffected hand compared to healthy controls. The body cooling correlated with mechanical hyperalgesia (Baron
areas of electrically induced pinprick hyperalgesia were et al. 2002). These findings indicate that in some neuro-
enhanced on the affected side (Seifert et al. 2009).These pathic pain syndromes sympathetic activity may directly
findings point to a reduced activity of endogenous pain induce nociceptive activation.
inhibiting systems in human neuropathic pain. Indirect mechanisms may contribute to sympathetically
A couple of substances which theoretically increase maintained pain as well. Increased sympathetically mediat-
inhibitory transmission are used for treating neuropathic ed vasomotor activity leads to altered microcirculation and
pain. Again, these are the noradrenalin and serotonin reuptake impaired nutrition and oxygenation (Kurvers et al. 1995). In
inhibitors, in particular tricyclic antidepressants, duloxetine this acidotic environment protons act as potent nociceptive
(Goldstein et al. 2005) and venlafaxine (Rowbotham et al. stimuli (Birklein et al. 2000). Also inflammation is in part
2004), opioid receptor agonists, and agents with GABAergic regulated by the sympathetic nervous system. For instance
properties like baclofen or valproate. The appealing bradykinin-induced plasma extravasation was shown to
perspective of subtype-selective GABAA receptor agonists depend on intact peripheral sympathetic structures (Miao
has recently been reviewed elsewhere (Zeilhofer et al. et al. 1996).
2009). Non-pharmacological treatment strategies – trans- Although the evidence is sparse (Cepeda et al. 2005)
cutaneous electrical nerve stimulation (TENS) and spinal regional sympathetic nerve block is applied in patients with
cord stimulation (SCS) – are also effective by modulating persistent CRPS. Also chemical and surgical sympathectomy
the inhibitory influence of pain transmission (Cruccu et al. is used. To our knowledge no clinical study has investigated
2007; Dubinsky and Miyasaki 2010). SCS was shown to the effect of α adrenoceptor blockers on neuropathic pain,
enhance inhibitory GABAergic signalling at the spinal dorsal though pathophysiologically this would be a reasonable
horn (Cui et al. 1997). It seems to inhibit spontaneous approach to sympathetically maintained pain.
discharge and response to mechanical stimuli of wide
dynamic range neurons at the spinal dorsal horn (Guan et
al. 2010). 7. Central reorganization processes

During the last years functional brain imaging has provided a


6. Sympathetically maintained pain powerful tool for investigating neuronal plasticity in the
central nervous system (CNS). Cortical reorganization pro-
The concept of sympathetically maintained pain is often cesses were found in some neuropathic pain syndromes, but
linked to the complex regional pain syndrome (CRPS). also in experimental pain models. Examples are CRPS and
However, fundamental principles are shared with other phantom limb pain. Today some features of these syn-
neuropathic pain syndromes like acute herpes zoster, dromes, which cannot be explained by peripheral mecha-
phantom limb pain, traumatic neuropathies, and plexus nisms, are taken to be adaptive changes in the CNS.
lesions. In these syndromes modulation of sympathetic Hemisensory phenomena and neglect-like symptoms in
activity – by means of a pharmacological sympathetic CRPS are examples (Frettloh et al. 2006).
block for example – may influence the pain course. Typically It is well known from animal studies that peripheral
the amount of pain related to sympathetic activity depends noxious stimuli determine central neuronal plasticity. For
on the disease stage. instance after partial ligation of the sciatic nerve in rats an
How do the anatomically distinct somatosensory and immediate reorganization of lateral thalamic networks and
autonomic nervous systems interact? Anesthetic blockage of changes in the somatosensory representation could be shown
the sympathetic trunk does not affect somatosensory (Bruggemann et al. 2001). Representation areas of noxiously
neurons directly. Generally there are direct and indirect stimulated body parts expand into areas of adjacent ones.
mechanisms contributing to sympathetically maintained The primary somatosensory projection area S1 shows a
pain. Animal studies showed nociceptive afferent fibers clear somatotopic arrangement. Imaging studies in patients
and sympathetic efferent fibers to be coupled. After with phantom limb pain revealed a significant reorganization
peripheral nerve lesions α adrenoceptors are expressed on of this region (Flor et al. 1995; Knecht et al. 1998). The
primary nociceptive fibers (Sato and Perl 1991), which amount of cortical reorganization was positively correlated
become responsive to catecholamines. In humans as well with pain intensity in these patients. This means that the
efferent sympathetic signaling seems to be coupled to more the representation area of non-involved body parts
nociceptive input in neuropathic pain. After successful shifted into the projection field of the amputated limb, the
therapeutic sympathetic block the subcutaneous application more intense the phantom pain was. These neuroplastic
of noradrenalin provoked similar pain sensations as before changes might be reversible by therapeutic interventions.
the intervention (Torebjork et al. 1995). After patients The use of a myoelectric prosthesis along with training in
Mechanisms of neuropathic pain 87

sensory discrimination can lead to alleviated pain and to a involved in the descending brain modulating system and
reduction of cortical reorganization (Flor 2002; Flor et al. promote pro- and antinociceptive effects (Tracey and
2001). Mantyh 2007). Physiologic and biochemical changes in
In CRPS as well cortical reorganization processes could be these regions during neuropathic pain are increasingly
shown. In contrast to phantom limb pain, CRPS type 1 is not recognized (Seifert and Maihofner 2009; Vanegas and
linked to traumatic nerve injury. However, several lines of Schaible 2004).
evidence suggest changes in somatosensory and motor Physical therapy addresses the cortical neuroplastic
representation. In CRPS type 1 the hand representation in changes. The Perfetti method and in particular the mirror
S1 shrunk, and the hand position was switched towards the box therapy seem to be effective in CRPS und phantom limb
lip (Maihofner et al. 2003). These changes correlated with pain (McCabe et al. 2008; Ramachandran and Altschuler
punctuate mechanical hyperalgesia. After treatment this 2009). Although stronger evidence is still lacking, repetitive
cortical reorganization was reversed and symptoms im- transcranial magnetic stimulation may also interfere with
proved (Fig. 2) (Maihofner et al. 2004). Using functional central reorganization processes and modify pain perception
MRI, adaptive motor changes in CRPS could also be shown. (Cruccu et al. 2007).
These reorganization processes correlated with motor
dysfunction and comprised increased activation of primary
7.1. Synthesis
motor cortices ipsilaterally and contralaterally and supple-
mentary motor cortices (Maihofner et al. 2007).
Neuropathic pain is the consequence of a complex
In other pain syndromes like chronic back pain and
interplay of mechanisms in the peripheral and central
peripheral nerve lesions, cortical reorganization processes
nervous system. Peripheral sensitization of the nociceptor
seem to play a role in the maladaptive central answer to
and abnormal excitability of nociceptive afferent fibers
chronic nociceptive input (Flor et al. 1997; Tecchio et al.
lead to enhanced afferent input at the spinal dorsal horn.
2002).
At the spinal level synaptic transmission is increased via
These presumably maladaptive cortical reorganization
pronociceptive activation and decreased inhibitory in-
processes result in a couple of phenomena, which are
fluences. Finally, central processing of somatosensory
otherwise not explainable. Examples are referred sensations
input is altered by cortical reorganization phenomena.
in the amputated limb by tactile stimulation of the
Future efforts will be made to correlate clinical signs with
ipsilateral face (Ramachandran et al. 1992) and somatosen-
different etiologies of neuropathic pain and to link them
sory abnormalities in CRPS, which are not attributable to one
with the pathophysiological concepts described above.
peripheral nerve or nerve root (Maihofner et al. 2006).
This may lead to a tailored and individualized therapy of
Apart from cortical changes also neuroplastic changes in
neuropathic pain.
thalamus and brain stem nuclei may occur in neuropathic
pain. For example, in patients with spontaneous pain due to
mononeuropathy and post-traumatic neuropathic pain, PET Role of funding sources
studies showed a reduced regional cerebral blood flow (rCBF)
in the contralateral thalamus (Hsieh et al. 1995; Iadarola et Funding for this study was provided by grants of the German
al. 1995). This finding may reflect a protection from ongoing Research Network “Neuropathic Pain” of the German Federal
nociceptive input. Brain stem nuclei like the periaqueductal Ministry of Education and Research (Bundesministerium für
grey (PAG) and the rostral ventral medulla (RVM) are Bildung und Forschung; BMBF), the German Research Foundation

Figure 2 Cortical reorganization processes in CRPS. A Cortical hand extension of the corresponding affected hand representation
between thumb (D1) and 5th digit (D5) was reduced compared to the contralateral side. B After treatment, the reduced cortical hand
extension of the affected side normalized. Projection of magnetoencephalographic data on MRI slices, modified from (Maihofner et al.
2004).
88 F.T. Nickel et al.

(Deutsche Forschungsgemeinschaft, KFO 130) and the ELAN- Fond Al-Gazali, L., Hamamy, H., Valente, E.M., Gorman, S., Williams,
of the University of Erlangen. All funding sources had no further R., McHale, D.P., Wood, J.N., Gribble, F.M., Woods, C.G., 2006.
role in the study design; in the collection, analysis and An SCN9A channelopathy causes congenital inability to experi-
interpretation of the data; in writing the manuscript; and in the ence pain. Nature 444, 894–898.
decision to submit the paper for publication. Craig, A.D., 2002. How do you feel? Interoception: the sense of the
physiological condition of the body. Nat Rev Neurosci 3, 655–666.
Craig, A.D., Bushnell, M.C., 1994. The thermal grill illusion:
Contributors unmasking the burn of cold pain. Science 265, 252–255.
Cruccu, G., Aziz, T.Z., Garcia-Larrea, L., Hansson, P., Jensen, T.S.,
Florian Nickel, Frank Seifert and Christian Maihöfner wrote the Lefaucheur, J.P., Simpson, B.A., Taylor, R.S., 2007. EFNS
article. Stefan Lanz managed the literature searches and guidelines on neurostimulation therapy for neuropathic pain.
analyses. All authors contributed to and have approved the final Eur J Neurol 14, 952–970.
manuscript. Cui, J.G., O'Connor, W.T., Ungerstedt, U., Linderoth, B., Meyerson,
B.A., 1997. Spinal cord stimulation attenuates augmented dorsal
horn release of excitatory amino acids in mononeuropathy via a
Conflict of interest GABAergic mechanism. Pain 73, 87–95.
Cummins, T.R., Sheets, P.L., Waxman, S.G., 2007. The roles of
We declare no conflict of interest. sodium channels in nociception: Implications for mechanisms of
pain. Pain 131, 243–257.
D'Mello, R., Dickenson, A.H., 2008. Spinal cord mechanisms of pain.
Acknowledgements Br J Anaesth 101, 8–16.
Dick, I.E., Brochu, R.M., Purohit, Y., Kaczorowski, G.J., Martin, W.J.,
Supported by the German Research Network “Neuropathic Pain” Priest, B.T., 2007. Sodium channel blockade may contribute to
of the German Federal Ministry of Education and Research the analgesic efficacy of antidepressants. J Pain 8, 315–324.
(Bundesministerium für Bildung und Forschung; BMBF), the Dubinsky, R.M., Miyasaki, J., 2010. Assessment: efficacy of
German Research Foundation (Deutsche Forschungsgemeinschaft, transcutaneous electric nerve stimulation in the treatment of
KFO 130) and the ELAN- Fond of the University of Erlangen. We pain in neurologic disorders (an evidence-based review): report
thank Conny Hofmann for excellent technical assistance. of the Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology. Neurology 74, 173–176.
Eide, P.K., Jorum, E., Stubhaug, A., Bremnes, J., Breivik, H.,
References 1994. Relief of post-herpetic neuralgia with the N-methyl-D-
aspartic acid receptor antagonist ketamine: a double-blind,
Abram, S.E., Yaksh, T.L., 1994. Systemic lidocaine blocks nerve cross-over comparison with morphine and placebo. Pain 58,
injury-induced hyperalgesia and nociceptor-driven spinal 347–354.
sensitization in the rat. Anesthesiology 80, 383–391 discussion 325A. Eisenberg, E., Lurie, Y., Braker, C., Daoud, D., Ishay, A., 2001.
Amir, R., Michaelis, M., Devor, M., 1999. Membrane potential Lamotrigine reduces painful diabetic neuropathy: a randomized,
oscillations in dorsal root ganglion neurons: role in normal controlled study. Neurology 57, 505–509.
electrogenesis and neuropathic pain. J Neurosci 19, 8589–8596. Fertleman, C.R., Baker, M.D., Parker, K.A., Moffatt, S., Elmslie, F.V.,
Baron, R., Schattschneider, J., Binder, A., Siebrecht, D., Wasner, Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J.N., Gardiner,
G., 2002. Relation between sympathetic vasoconstrictor activity R.M., Rees, M., 2006. SCN9A mutations in paroxysmal extreme pain
and pain and hyperalgesia in complex regional pain syndromes: a disorder: allelic variants underlie distinct channel defects and
case-control study. Lancet 359, 1655–1660. phenotypes. Neuron 52, 767–774.
Bird, E.V., Robinson, P.P., Boissonade, F.M., 2007. Na(v)1.7 sodium Flor, H., 2002. Phantom-limb pain: characteristics, causes, and
channel expression in human lingual nerve neuromas. Arch Oral treatment. Lancet Neurol 1, 182–189.
Biol 52, 494–502. Flor, H., Braun, C., Elbert, T., Birbaumer, N., 1997. Extensive
Birklein, F., Weber, M., Ernst, M., Riedl, B., Neundorfer, B., reorganization of primary somatosensory cortex in chronic back
Handwerker, H.O., 2000. Experimental tissue acidosis leads to pain patients. Neurosci Lett 224, 5–8.
increased pain in complex regional pain syndrome (CRPS). Pain Flor, H., Denke, C., Schaefer, M., Grusser, S., 2001. Effect of sensory
87, 227–234. discrimination training on cortical reorganisation and phantom
Bouhassira, D., 2008. Definition and classification of neuropathic limb pain. Lancet 357, 1763–1764.
pain. Presse Med 37, 311–314. Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C.,
Brochu, R.M., Dick, I.E., Tarpley, J.W., McGowan, E., Gunner, D., Birbaumer, N., Larbig, W., Taub, E., 1995. Phantom-limb pain
Herrington, J., Shao, P.P., Ok, D., Li, C., Parsons, W.H., Stump, as a perceptual correlate of cortical reorganization following arm
G.L., Regan, C.P., Lynch Jr., J.J., Lyons, K.A., McManus, O.B., amputation. Nature 375, 482–484.
Clark, S., Ali, Z., Kaczorowski, G.J., Martin, W.J., Priest, B.T., Flor, H., Nikolajsen, L., Staehelin Jensen, T., 2006. Phantom limb
2006. Block of peripheral nerve sodium channels selectively pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci 7,
inhibits features of neuropathic pain in rats. Mol Pharmacol 69, 873–881.
823–832. Frettloh, J., Huppe, M., Maier, C., 2006. Severity and specificity of
Bruggemann, J., Galhardo, V., Apkarian, A.V., 2001. Immediate neglect-like symptoms in patients with complex regional pain
reorganization of the rat somatosensory thalamus after partial syndrome (CRPS) compared to chronic limb pain of other origins.
ligation of sciatic nerve. J Pain 2, 220–228. Pain 124, 184–189.
Cepeda, M.S., Carr, D.B., Lau, J., 2005. Local anesthetic sympa- Freynhagen, R., Baron, R., 2009. The evaluation of neuropathic
thetic blockade for complex regional pain syndrome. Cochrane components in low back pain. Curr Pain Headache Rep 13,
Database Syst Rev, CD004598. 185–190.
Costigan, M., Woolf, C.J., 2002. No DREAM, No pain. Closing the Freynhagen, R., Rolke, R., Baron, R., Tolle, T.R., Rutjes, A.K., Schu,
spinal gate. Cell 108, 297–300. S., Treede, R.D., 2008. Pseudoradicular and radicular low-back
Cox, J.J., Reimann, F., Nicholas, A.K., Thornton, G., Roberts, E., pain–a disease continuum rather than different entities? Answers
Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., from quantitative sensory testing. Pain 135, 65–74.
Mechanisms of neuropathic pain 89

Fundytus, M.E., Fisher, K., Dray, A., Henry, J.L., Coderre, T.J., Kawasaki, Y., Xu, Z.Z., Wang, X., Park, J.Y., Zhuang, Z.Y., Tan, P.H.,
1998. In vivo antinociceptive activity of anti-rat mGluR1 and Gao, Y.J., Roy, K., Corfas, G., Lo, E.H., Ji, R.R., 2008. Distinct
mGluR5 antibodies in rats. Neuroreport 9, 731–735. roles of matrix metalloproteases in the early- and late-phase
Gilron, I., 2007. Gabapentin and pregabalin for chronic neuropathic development of neuropathic pain. Nat Med 14, 331–336.
and early postsurgical pain: current evidence and future di- Khasabov, S.G., Rogers, S.D., Ghilardi, J.R., Peters, C.M., Mantyh,
rections. Curr Opin Anaesthesiol 20, 456–472. P.W., Simone, D.A., 2002. Spinal neurons that possess the
Gilron, I., Watson, C.P., Cahill, C.M., Moulin, D.E., 2006. Neuro- substance P receptor are required for the development of central
pathic pain: a practical guide for the clinician. Cmaj 175, sensitization. J Neurosci 22, 9086–9098.
265–275. Kiefer, R.T., Rohr, P., Ploppa, A., Dieterich, H.J., Grothusen, J.,
Goldstein, D.J., Lu, Y., Detke, M.J., Lee, T.C., Iyengar, S., 2005. Koffler, S., Altemeyer, K.H., Unertl, K., Schwartzman, R.J.,
Duloxetine vs. placebo in patients with painful diabetic 2008. Efficacy of ketamine in anesthetic dosage for the
neuropathy. Pain 116, 109–118. treatment of refractory complex regional pain syndrome: an
Guan, Y., Wacnik, P.W., Yang, F., Carteret, A.F., Chung, C.Y., open-label phase II study. Pain Med 9, 1173–1201.
Meyer, R.A., Raja, S.N., 2010. Spinal cord stimulation-induced Knabl, J., Witschi, R., Hosl, K., Reinold, H., Zeilhofer, U.B., Ahmadi,
analgesia: electrical stimulation of dorsal column and dorsal S., Brockhaus, J., Sergejeva, M., Hess, A., Brune, K., Fritschy, J.M.,
roots attenuates dorsal horn neuronal excitability in neuropathic Rudolph, U., Mohler, H., Zeilhofer, H.U., 2008. Reversal of
rats. Anesthesiology 113, 1392–1405. pathological pain through specific spinal GABAA receptor subtypes.
Guerrini, R., Parmeggiani, L., 2006. Topiramate and its clinical Nature 451, 330–334.
applications in epilepsy. Expert Opin Pharmacother 7, 811–823. Knecht, S., Henningsen, H., Hohling, C., Elbert, T., Flor, H., Pantev,
Guo, L.H., Schluesener, H.J., 2007. The innate immunity of the C., Taub, E., 1998. Plasticity of plasticity? Changes in the pattern
central nervous system in chronic pain: the role of Toll-like of perceptual correlates of reorganization after amputation.
receptors. Cell Mol Life Sci 64, 1128–1136. Brain 121 (Pt 4), 717–724.
Han, C., Rush, A.M., Dib-Hajj, S.D., Li, S., Xu, Z., Wang, Y., Tyrrell, Koppert, W., Dern, S.K., Sittl, R., Albrecht, S., Schuttler, J.,
L., Wang, X., Yang, Y., Waxman, S.G., 2006. Sporadic onset of Schmelz, M., 2001. A new model of electrically evoked pain and
erythermalgia: a gain-of-function mutation in Nav1.7. Ann hyperalgesia in human skin: the effects of intravenous alfentanil,
Neurol 59, 553–558. S(+)-ketamine, and lidocaine. Anesthesiology 95, 395–402.
Hansson, P., Backonja, M., Bouhassira, D., 2007. Usefulness and Kurvers, H.A., Jacobs, M.J., Beuk, R.J., Van den Wildenberg, F.A.,
limitations of quantitative sensory testing: clinical and research Kitslaar, P.J., Slaaf, D.W., Reneman, R.S., 1995. Reflex
application in neuropathic pain states. Pain 129, 256–259. sympathetic dystrophy: evolution of microcirculatory distur-
Hong, S., Morrow, T.J., Paulson, P.E., Isom, L.L., Wiley, J.W., 2004. bances in time. Pain 60, 333–340.
Early painful diabetic neuropathy is associated with differential Lai, J., Luo, M.C., Chen, Q., Ma, S., Gardell, L.R., Ossipov, M.H.,
changes in tetrodotoxin-sensitive and -resistant sodium channels Porreca, F., 2006. Dynorphin A activates bradykinin receptors to
in dorsal root ganglion neurons in the rat. J Biol Chem 279, maintain neuropathic pain. Nat Neurosci 9, 1534–1540.
29341–29350. Lingueglia, E., 2007. Acid-sensing ion channels in sensory percep-
Hong, S., Wiley, J.W., 2005. Early painful diabetic neuropathy is tion. J Biol Chem 282, 17325–17329.
associated with differential changes in the expression and Lumpkin, E.A., Caterina, M.J., 2007. Mechanisms of sensory
function of vanilloid receptor 1. J Biol Chem 280, 618–627. transduction in the skin. Nature 445, 858–865.
Hsieh, J.C., Belfrage, M., Stone-Elander, S., Hansson, P., Ingvar, M., Luo, Z.D., Chaplan, S.R., Higuera, E.S., Sorkin, L.S., Stauderman, K.A.,
1995. Central representation of chronic ongoing neuropathic pain Williams, M.E., Yaksh, T.L., 2001. Upregulation of dorsal root
studied by positron emission tomography. Pain 63, 225–236. ganglion (alpha)2(delta) calcium channel subunit and its correlation
Hucho, T., Levine, J.D., 2007. Signaling pathways in sensitization: with allodynia in spinal nerve-injured rats. J Neurosci 21, 1868–1875.
toward a nociceptor cell biology. Neuron 55, 365–376. Maihofner, C., Baron, R., DeCol, R., Binder, A., Birklein, F., Deuschl,
Hudson, L.J., Bevan, S., Wotherspoon, G., Gentry, C., Fox, A., G., Handwerker, H.O., Schattschneider, J., 2007. The motor
Winter, J., 2001. VR1 protein expression increases in undamaged system shows adaptive changes in complex regional pain
DRG neurons after partial nerve injury. Eur J Neurosci 13, syndrome. Brain 130, 2671–2687.
2105–2114. Maihofner, C., Handwerker, H.O., Neundorfer, B., Birklein, F., 2003.
Iadarola, M.J., Max, M.B., Berman, K.F., Byas-Smith, M.G., Coghill, Patterns of cortical reorganization in complex regional pain
R.C., Gracely, R.H., Bennett, G.J., 1995. Unilateral decrease in syndrome. Neurology 61, 1707–1715.
thalamic activity observed with positron emission tomography in Maihofner, C., Handwerker, H.O., Neundorfer, B., Birklein, F., 2004.
patients with chronic neuropathic pain. Pain 63, 55–64. Cortical reorganization during recovery from complex regional
Inoue, M., Rashid, M.H., Fujita, R., Contos, J.J., Chun, J., Ueda, H., pain syndrome. Neurology 63, 693–701.
2004. Initiation of neuropathic pain requires lysophosphatidic Maihofner, C., Neundorfer, B., Birklein, F., Handwerker, H.O., 2006.
acid receptor signaling. Nat Med 10, 712–718. Mislocalization of tactile stimulation in patients with complex
Jarvis, B., Coukell, A.J., 1998. Mexiletine. A review of its regional pain syndrome. J Neurol 253, 772–779.
therapeutic use in painful diabetic neuropathy. Drugs 56, Malan, T.P., Ossipov, M.H., Gardell, L.R., Ibrahim, M., Bian, D., Lai,
691–707. J., Porreca, F., 2000. Extraterritorial neuropathic pain correlates
Jarvis, M.F., Honore, P., Shieh, C.C., Chapman, M., Joshi, S., Zhang, with multisegmental elevation of spinal dynorphin in nerve-
X.F., Kort, M., Carroll, W., Marron, B., Atkinson, R., Thomas, J., injured rats. Pain 86, 185–194.
Liu, D., Krambis, M., Liu, Y., McGaraughty, S., Chu, K., Roeloffs, Manfredi, M., Bini, G., Cruccu, G., Accornero, N., Berardelli, A.,
R., Zhong, C., Mikusa, J.P., Hernandez, G., Gauvin, D., Wade, C., Medolago, L., 1981. Congenital absence of pain. Arch Neurol 38,
Zhu, C., Pai, M., Scanio, M., Shi, L., Drizin, I., Gregg, R., 507–511.
Matulenko, M., Hakeem, A., Gross, M., Johnson, M., Marsh, K., Matthews, E.A., Dickenson, A.H., 2001. Effects of spinally delivered
Wagoner, P.K., Sullivan, J.P., Faltynek, C.R., Krafte, D.S., 2007. N- and P-type voltage-dependent calcium channel antagonists on
A-803467, a potent and selective Nav1.8 sodium channel blocker, dorsal horn neuronal responses in a rat model of neuropathy. Pain
attenuates neuropathic and inflammatory pain in the rat. Proc 92, 235–246.
Natl Acad Sci USA 104, 8520–8525. McCabe, C.S., Haigh, R.C., Blake, D.R., 2008. Mirror visual feedback
Julius, D., Basbaum, A.I., 2001. Molecular mechanisms of nocicep- for the treatment of complex regional pain syndrome (type 1).
tion. Nature 413, 203–210. Curr Pain Headache Rep 12, 103–107.
90 F.T. Nickel et al.

McDermott, A.M., Toelle, T.R., Rowbotham, D.J., Schaefer, C.P., Seifert, F., Maihofner, C., 2009. Central mechanisms of experimen-
Dukes, E.M., 2006. The burden of neuropathic pain: results from tal and chronic neuropathic pain: findings from functional
a cross-sectional survey. Eur J Pain 10, 127–135. imaging studies. Cell Mol Life Sci 66, 375–390.
Miao, F.J., Janig, W., Levine, J., 1996. Role of sympathetic Shinder, V., Govrin-Lippmann, R., Cohen, S., Belenky, M., Ilin, P.,
postganglionic neurons in synovial plasma extravasation induced Fried, K., Wilkinson, H.A., Devor, M., 1999. Structural basis of
by bradykinin. J Neurophysiol 75, 715–724. sympathetic-sensory coupling in rat and human dorsal root
Moalem, G., Tracey, D.J., 2006. Immune and inflammatory ganglia following peripheral nerve injury. J Neurocytol 28,
mechanisms in neuropathic pain. Brain Res Rev 51, 240–264. 743–761.
Ossipov, M.H., Lai, J., Malan Jr., T.P., Porreca, F., 2000. Spinal and Simpson, D.M., McArthur, J.C., Olney, R., Clifford, D., So, Y., Ross,
supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci D., Baird, B.J., Barrett, P., Hammer, A.E., 2003. Lamotrigine for
909, 12–24. HIV-associated painful sensory neuropathies: a placebo-con-
Pan, H.L., Wu, Z.Z., Zhou, H.Y., Chen, S.R., Zhang, H.M., Li, D.P., trolled trial. Neurology 60, 1508–1514.
2008. Modulation of pain transmission by G-protein-coupled Sommer, C., Kress, M., 2004. Recent findings on how proinflamma-
receptors. Pharmacol Ther 117, 141–161. tory cytokines cause pain: peripheral mechanisms in inflamma-
Pezet, S., McMahon, S.B., 2006. Neurotrophins: mediators and tory and neuropathic hyperalgesia. Neurosci Lett 361, 184–187.
modulators of pain. Annu Rev Neurosci 29, 507–538. Susser, E., Sprecher, E., Yarnitsky, D., 1999. Paradoxical heat
Ramachandran, V.S., Altschuler, E.L., 2009. The use of visual sensation in healthy subjects: peripherally conducted by A delta
feedback, in particular mirror visual feedback, in restoring brain or C fibres? Brain 122 (Pt 2), 239–246.
function. Brain 132, 1693–1710. Suzuki, R., Hunt, S.P., Dickenson, A.H., 2003. The coding of noxious
Ramachandran, V.S., Stewart, M., Rogers-Ramachandran, D.C., mechanical and thermal stimuli of deep dorsal horn neurones is
1992. Perceptual correlates of massive cortical reorganization. attenuated in NK1 knockout mice. Neuropharmacology 45,
Neuroreport 3, 583–586. 1093–1100.
Ramer, M.S., Thompson, S.W., McMahon, S.B., 1999. Causes and Tal, M., Wall, P.D., Devor, M., 1999. Myelinated afferent fiber
consequences of sympathetic basket formation in dorsal root types that become spontaneously active and mechanosensi-
ganglia. Pain Suppl 6, S111–S120. tive following nerve transection in the rat. Brain Res 824,
Raskin, P., Donofrio, P.D., Rosenthal, N.R., Hewitt, D.J., Jordan, 218–223.
D.M., Xiang, J., Vinik, A.I., 2004. Topiramate vs placebo in Tecchio, F., Padua, L., Aprile, I., Rossini, P.M., 2002. Carpal tunnel
painful diabetic neuropathy: analgesic and metabolic effects. syndrome modifies sensory hand cortical somatotopy: a MEG
Neurology 63, 865–873. study. Hum Brain Mapp 17, 28–36.
Rauck, R.L., Wallace, M.S., Leong, M.S., Minehart, M., Webster, L.R., Thienel, U., Neto, W., Schwabe, S.K., Vijapurkar, U., 2004.
Charapata, S.G., Abraham, J.E., Buffington, D.E., Ellis, D., Topiramate in painful diabetic polyneuropathy: findings from
Kartzinel, R., 2006. A randomized, double-blind, placebo- three double-blind placebo-controlled trials. Acta Neurol Scand
controlled study of intrathecal ziconotide in adults with severe 110, 221–231.
chronic pain. J Pain Symptom Manage 31, 393–406. Torebjork, E., Wahren, L., Wallin, G., Hallin, R., Koltzenburg, M.,
Rice, A.S., Hill, R.G., 2006. New treatments for neuropathic pain. 1995. Noradrenaline-evoked pain in neuralgia. Pain 63, 11–20.
Annu Rev Med 57, 535–551. Torrance, N., Smith, B.H., Bennett, M.I., Lee, A.J., 2006. The
Ro, L.S., Chen, S.T., Tang, L.M., Jacobs, J.M., 1999. Effect of NGF epidemiology of chronic pain of predominantly neuropathic
and anti-NGF on neuropathic pain in rats following chronic origin. Results from a general population survey. J Pain 7,
constriction injury of the sciatic nerve. Pain 79, 265–274. 281–289.
Rogers, M., Tang, L., Madge, D.J., Stevens, E.B., 2006. The role of Tracey, I., Mantyh, P.W., 2007. The cerebral signature for pain
sodium channels in neuropathic pain. Semin Cell Dev Biol 17, perception and its modulation. Neuron 55, 377–391.
571–581. Treede, R.D., Jensen, T.S., Campbell, J.N., Cruccu, G., Dostrovsky,
Rolke, R., Magerl, W., Campbell, K.A., Schalber, C., Caspari, S., J.O., Griffin, J.W., Hansson, P., Hughes, R., Nurmikko, T., Serra,
Birklein, F., Treede, R.D., 2006. Quantitative sensory testing: a J., 2008. Neuropathic pain: redefinition and a grading system for
comprehensive protocol for clinical trials. Eur J Pain 10, 77–88. clinical and research purposes. Neurology 70, 1630–1635.
Rowbotham, M.C., Goli, V., Kunz, N.R., Lei, D., 2004. Venlafaxine Tremont-Lukats, I.W., Challapalli, V., McNicol, E.D., Lau, J., Carr,
extended release in the treatment of painful diabetic neuropa- D.B., 2005. Systemic administration of local anesthetics to
thy: a double-blind, placebo-controlled study. Pain 110, relieve neuropathic pain: a systematic review and meta-analysis.
697–706. Anesth Analg 101, 1738–1749.
Roza, C., Laird, J.M., Souslova, V., Wood, J.N., Cervero, F., 2003. Tsuda, M., Inoue, K., Salter, M.W., 2005. Neuropathic pain and
The tetrodotoxin-resistant Na + channel Nav1.8 is essential for spinal microglia: a big problem from molecules in "small" glia.
the expression of spontaneous activity in damaged sensory axons Trends Neurosci 28, 101–107.
of mice. J Physiol 550, 921–926. Ueda, H., 2008. Peripheral mechanisms of neuropathic pain -
Sato, J., Perl, E.R., 1991. Adrenergic excitation of cutaneous pain involvement of lysophosphatidic acid receptor-mediated demy-
receptors induced by peripheral nerve injury. Science 251, elination. Mol Pain 4, 11.
1608–1610. Vanderah, T.W., Gardell, L.R., Burgess, S.E., Ibrahim, M., Dogrul,
Schmidt, R., Schmelz, M., Forster, C., Ringkamp, M., Torebjork, E., A., Zhong, C.M., Zhang, E.T., Malan Jr., T.P., Ossipov, M.H., Lai,
Handwerker, H., 1995. Novel classes of responsive and unre- J., Porreca, F., 2000. Dynorphin promotes abnormal pain and
sponsive C nociceptors in human skin. J Neurosci 15, 333–341. spinal opioid antinociceptive tolerance. J Neurosci 20,
Scholz, J., Mannion, R.J., Hord, D.E., Griffin, R.S., Rawal, B., Zheng, 7074–7079.
H., Scoffings, D., Phillips, A., Guo, J., Laing, R.J., Abdi, S., Vanegas, H., Schaible, H.G., 2004. Descending control of persistent
Decosterd, I., Woolf, C.J., 2009. A novel tool for the assessment pain: inhibitory or facilitatory? Brain Res Brain Res Rev 46,
of pain: validation in low back pain. PLoS Med 6, e1000047. 295–309.
Scholz, J., Woolf, C.J., 2007. The neuropathic pain triad: neurons, Vestergaard, K., Andersen, G., Gottrup, H., Kristensen, B.T.,
immune cells and glia. Nat Neurosci 10, 1361–1368. Jensen, T.S., 2001. Lamotrigine for central poststroke pain: a
Seifert, F., Kiefer, G., DeCol, R., Schmelz, M., Maihofner, C., 2009. randomized controlled trial. Neurology 56, 184–190.
Differential endogenous pain modulation in complex-regional White, D.M., Leah, J.D., Zimmermann, M., 1989. The localization
pain syndrome. Brain 132, 788–800. and release of substance P and calcitonin gene-related peptide at
Mechanisms of neuropathic pain 91

nerve fibre endings in rat cutaneous nerve neuroma. Brain Res Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu,
503, 198–204. B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y., 2004.
Wiffen, P.J., Rees, J., 2007. Lamotrigine for acute and chronic pain. Mutations in SCN9A, encoding a sodium channel alpha subunit, in
Cochrane Database Syst Rev, CD006044. patients with primary erythermalgia. J Med Genet 41, 171–174.
Wood, J.N., Boorman, J.P., Okuse, K., Baker, M.D., 2004. Voltage- Yarnitsky, D., 1997. Quantitative sensory testing. Muscle Nerve 20,
gated sodium channels and pain pathways. J Neurobiol 61, 55–71. 198–204.
Woolf, C.J., Decosterd, I., 1999. Implications of recent advances in Zeilhofer, H.U., 2008. Loss of glycinergic and GABAergic inhibition in
the understanding of pain pathophysiology for the assessment of chronic pain–contributions of inflammation and microglia. Int
pain in patients. Pain Suppl 6, S141–S147. Immunopharmacol 8, 182–187.
Woolf, C.J., Mannion, R.J., 1999. Neuropathic pain: aetiology, Zeilhofer, H.U., Witschi, R., Hosl, K., 2009. Subtype-selective GABA
symptoms, mechanisms, and management. Lancet 353, (A) receptor mimetics-novel antihyperalgesic agents? J Mol Med.
1959–1964. Zimmermann, K., Leffler, A., Babes, A., Cendan, C.M., Carr, R.W.,
Woolf, C.J., Salter, M.W., 2000. Neuronal plasticity: increasing the Kobayashi, J., Nau, C., Wood, J.N., Reeh, P.W., 2007. Sensory
gain in pain. Science 288, 1765–1769. neuron sodium channel Nav1.8 is essential for pain at low
Wu, W.L., Burnett, D.A., Domalski, M., Greenlee, W.J., Li, C., temperatures. Nature 447, 855–858.
Bertorelli, R., Fredduzzi, S., Lozza, G., Veltri, A., Reggiani, A., Zimmermann, M., 2001. Pathobiology of neuropathic pain. Eur J
2007. Discovery of orally efficacious tetracyclic metabotropic Pharmacol 429, 23–37.
glutamate receptor 1 (mGluR1) antagonists for the treatment of Zurborg, S., Yurgionas, B., Jira, J.A., Caspani, O., Heppenstall, P.A.,
chronic pain. J Med Chem 50, 5550–5553. 2007. Direct activation of the ion channel TRPA1 by Ca2+. Nat
Xing, H., Chen, M., Ling, J., Tan, W., Gu, J.G., 2007. TRPM8 Neurosci 10, 277–279.
mechanism of cold allodynia after chronic nerve injury. J
Neurosci 27, 13680–13690.