Signaling pathways in sensitization: toward a nociceptor cell biology.

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basis of transducers for noxious stimuli has incre
tracellular signaling mechanisms regulating nociceptor sensitization downstream of ligand binding
to the receptors is still at a relatively nascent stage. After outlining the initiated signaling cascades,
we discuss the emerging plasticity within these cascades and the importance of subcellular compart-
mentalization. In addition, the recently realized importance of functional interactions with the extra-
cellular matrix, cytoskeleton, intracellular organelles such as mitochondria, and sex hormones will
be introduced. This burgeoning literature establishes new cellular features crucial for the function
of nociceptive neurons and argues that additional focus should be placed on understanding the
complex integration of cellular events that make up the ‘‘cell biology of pain.’’
Introduction
From prokaryotes to higher eukaryotes, the complexity of
cellular organization expandedgreatly. Cell compartments
such as membrane-enclosed organelles and protein
clusters at functional sites evolved. In higher eukaryotes,
a multitude of specialized cells interact in a time- and
tissue-dependent manner. This increase in organizational
complexity is the necessary basis for the ability to integrate
increasing quantities and qualities of information about
the external as well as internal condition of the organism.
Sensory neurons in vertebrates connect peripheral tis-
sues with the central nervous system, occupying a partic-
ularly prominent position in acute information reception,
transduction, and integration. But they also show the po-
tential to undergo long-lasting plastic changes. This plas-
ticity, often in the form of sensitization, memory for prior
injury, or desensitization, can be beneficial in the case of
avoidance of physical stimulation of injured tissue. In con-
trast, in cases of chronic inflammatory or neuropathic
pain, these changes produce an often disabling burden
on the organism.
Nociceptive neuron sensitivity is modulated by a large
2002; Figure 1). How this multitude of cascades mediates
nociceptor sensitization and pain is only beginning to be
understood. As function relies upon structure, investiga-
tion of the cellular components involved in this process
has greatly enhanced the understanding of nociceptive
mechanisms and their modulation and opened surprising
new fields of research.
We review the existing data establishing the importance
of classical intracellular signaling components in inflam-
matory and neuropathic pain. Often in nociceptive neu-
rons the cascade-initiating receptor(s) has not been fully
characterized. Thus, we sort data according to the core
components of the respective signaling cascade. This
also avoids confusion, as signaling pathways can be acti-
vated and/or modulated by more than one receptor. This
overview is then followed by the introduction of two com-
plementary models that might integrate this data. The
models intrinsic logic highlights the need for furthering
our understanding of the basic cell-biological mecha-
nisms that impact nociceptor signaling. And indeed, as
exemplified by pioneering works, the complex cellular
organization of nociceptive neurons (e.g., subcellularNeuron
Review
Signaling Pathways in Se
Toward a Nociceptor Ce
Tim Hucho1,* and Jon D. Levine2
1Max Planck Institute for Molecular Genetics, 14195 Berlin, Ge
2University of California, San Francisco, San Francisco, CA 941
*Correspondence: hucho@molgen.mpg.de
DOI 10.1016/j.neuron.2007.07.008
Clinical pain is a serious public health issue. Tre
edge of howpain signals are initially interpreted
This review article is one of three reviews in this
of the pain process and possible solutions to th
viewpoints.
The electrophysiological properties of periphera
afferent nociceptors, have been investigated intvariety of mediators in the extracellular space. These me-
diators activate a large number of receptor classes, which
in turn activate a plethora of signaling cascades (Julius
and Basbaum, 2001; Lewin et al., 2004; Scholz andWoolf,nsitization:
l Biology
many
43, USA
atment of pain-related suffering requires knowl-
and subsequently transmitted and perpetuated.
issue of Neuron that address our understanding
e problem from both cellular- and systems-level
neurons activated by noxious stimuli, the primary
nsively, and our knowledge about the molecular
ased greatly. In contrast, understanding of the in-compartmentalization, signaling cascade plasticity, extra-
cellular matrix components, the cytoskeleton, intracellular
organelles, and sex hormones) is essential for its function.
We will argue that a thorough investigation of these
Neuron 55, August 2, 2007 ª2007 Elsevier Inc. 365

components of the intracellular signaling machinery is
essential in order to fully understand how nociceptive cas-
cades function. Additionally, by elucidating new compo-
nents of this signaling cascade, such basic cell-biological
research should also help to identify potential new thera-
peutic targets for management of pain.
Nociceptor Signaling Pathway Components
cAMP and Protein Kinase A (PKA)
The first cellular second messenger discovered, cAMP,
was also the first implicated in pain and nociceptor sensi-
tization. Indeed, intradermal injection of membrane-
permeable cAMP analogs (Ferreira et al., 1990; Taiwo
et al., 1989) or the adenylyl cyclase activator forskolin
(Taiwo and Levine, 1991), produce robust sensitization to-
ward physical stimuli (hyperalgesia) and sensitization of
nociceptive fibers (Kress et al., 1996). Inflammatory medi-
ators such as prostaglandins result in increased intracellu-
lar cAMP and lead to hyperalgesia, which can be blocked
by the inactive cAMP analog, Rp-cAMP (Taiwo and Lev-
ine, 1991). The inflammation-induced increase in cAMP
also induces cellular correlates of pain such as increased
evoked transmitter release (Hingtgen et al., 1995) and
modulates voltage (England et al., 1996; Gold et al.,
1998) and ligand-gated ion channels important in pain
(Lopshire and Nicol, 1998; Pitchford and Levine, 1991).
Not only the onset but also the duration of hyperalgesia
Figure 1. Signaling Components in Nociceptors
A large number of extracellular mediators modulate nociception. They
act through several receptor classes. Thereby, a plethora of intracellu-
lar signaling cascades is initiated. So far, research has concentrated
on verifying the involvement of core components of these pathways
mostly neglecting the identification of upstream aswell as downstream
signaling components. Only few downstream effectors (red ovals)
such as ion channels have been identified, the discussion of which is
beyond the scope of this review. As none of the components charac-
terized so far fully explains the process of sensitization, further cellular
components have to be investigated.is dependent on continuously elevated cAMP levels.
Thus, Rp-cAMP reduces hyperalgesia even if injected af-
ter hyperalgesia is already established (Aley and Levine,
1999; Taiwo and Levine, 1991). The intracellular cAMP
366 Neuron 55, August 2, 2007 ª2007 Elsevier Inc.concentration in nociceptive neurons can be reduced by
activation of endogenous m-, d-, and k-opioid receptors,
which may be, in part, responsible for the peripheral
antinociceptive actions of morphine and other opioids
(Aley and Levine, 1997; Collier and Roy, 1974; Ferreira
and Nakamura, 1979; Stein et al., 1989). Long-term expo-
sure to opioids results in desensitization of the opioid
receptors and compensatory production of cAMP accom-
panied by loss of the antinociceptive effect of opioids
(Nestler, 2004).
cAMP signaling is widely held to be synonymous with
the activity of its binding partner, protein kinase A (PKA).
Pharmacological as well as genetic inhibition of PKA, re-
sults in a reduction of inflammatory mediator-induced
hyperalgesic behavior (Aley and Levine, 1999; Malmberg
et al., 1997), in reduced nociceptor discharge (Cui and
Nicol, 1995; Zhang et al., 2002a), as well as in attenuated
stimulus-induced peptide release (Oshita et al., 2005).
While the exact mechanisms of these PKA-mediated
effects are not fully understood, mutation of PKA phos-
phorylation sites on effector ion channels such as the pri-
mary afferent nociceptor specific, tetrodotoxin-resistant
sodium channel, NaV1.8 (TTX-R INa) (Fitzgerald et al.,
1999) and the ligand-gated ion channel TRPV1 (Bhave
et al., 2002) results in ablation of channel modulation by
PKA.
It has recently become clear that cAMP can also acti-
vate molecules other than PKA such as calcium channels
(reviewed by Kaupp and Seifert, 2002) and the GDP/GTP
exchange factor Epac (de Rooij et al., 1998; Kawasaki
et al., 1998; see discussion below). Therefore, some of
the established data on cAMP signaling pathways in noci-
ceptor sensitization must also take these additional
targets into consideration (Hucho et al., 2005). While
cAMP/PKA signaling is important for inflammatory hyper-
algesia, it is also clear that other second messenger path-
ways play critical roles in this process.
Protein Kinase C (PKC)
There is an extensive literature documenting a role of
PKC in nociceptor activation as well as sensitization.
PKC activating phorbol esters and inflammatory media-
tors cause long-lasting nociceptive behaviors (Souza
et al., 2002) and depolarize as well as activate nociceptors
(Burgess et al., 1989b; Dray et al., 1988; Rang and Ritchie,
1988).
Also, sensitization of nociceptors can be induced in
a PKC dependent manner, as measured by thermal and
mechanical hyperalgesia (Souza et al., 2002), mechani-
cally induced nociceptor activity in knee joint afferents
(Schepelmann et al., 1993), thermally induced secretion
of neuropeptides from the peripheral terminals of afferents
(Cesare et al., 1999; Kessler et al., 1999), as well as
increase of TTX-R INa in DRG neurons (Cesare and
McNaughton, 1996; Gold et al., 1996). Treatment of
Neuron
ReviewTRPV1 expressing cells with phorbol esters lowers the
heat-threshold of TRPV1 below body temperature and
sensitizes TRPV1 expressing cells to stimulation by cap-
saicin (Crandall et al., 2002; Premkumar and Ahern,

2000). The mechanism of this effect appears to involve di-
rect phosphorylation (Bhave et al., 2003; Mandadi et al.,
2006; Numazaki et al., 2002) leading to, among other
changes, PKC-dependent insertion of TRPV1 channels
into the plasma membrane (Morenilla-Palao et al., 2004;
Van Buren et al., 2005).
At least six PKC isoforms (a, bI, bII, d, 3, z) have been
detected in DRG neurons. But only PKC3, a member of
the calcium-independent novel PKCs, has been shown
to be activated by the inflammatory mediators bradykinin,
epinephrine, carrageenan, tumor necrosis factor alpha
(TNFa), and the protease-activated receptor (PAR2) and
to mediate sensitization to mechanical and thermal stimuli
(Amadesi et al., 2006; Cesare et al., 1999; Khasar et al.,
1999a; Olah et al., 2002; Parada et al., 2003a). In a PKC3
knockout mouse, the basal threshold to mechanical as
well as thermal stimulation was unchanged. In contrast,
sensitization in response to inflammatory mediator treat-
ment was much reduced (Khasar et al., 1999b). Indeed,
sensitization of the nociceptor specific TTX-R INa was
dependent on PKC3 activity (Khasar et al., 1999b), and
enhanced activity of another ion channel important in
inflammatory pain, TRPV1, was shown to require direct
phosphorylation of TRPV1 by PKC3 (Bhave et al., 2003;
Mandadi et al., 2006; Numazaki et al., 2002).
Beyond inflammatory mediator-induced sensitization
PKC3 is involved in various models of neuropathic pain,
such as that associated with diabetes (Joseph and Levine,
2003b), chronic alcoholism (Dina et al., 2000), and cancer
chemotherapy (Dina et al., 2001b; Joseph and Levine,
2003a). In addition, PKC3 activity widens the generally ac-
cepted dichotomy of naive and sensitized nociceptors by
defining the novel ‘‘primed state’’ (see discussion below
and Figure 3). Interestingly, PKC3 signaling in primary af-
ferent nociceptors was found to depend on cytoskeleton
and cell membrane microdomains (expanded upon
below), exemplifying the need to investigate other cellular
aspects than electrophysiological properties and kinase
activation states for nociceptor sensitization.
Mitogen-Activated Protein Kinases (MAPK)
Mitogen-activated protein kinases (MAPKs) have also
recently been implicated in nociceptor sensitization asso-
ciated with inflammation and peripheral neuropathy. Acti-
vation of ERK1/2 by b2-adrenergic agonists contributes to
mechanical hyperalgesia (Aley et al., 2001). In nocicep-
tors, ERK is also activated by NGF (Averill et al., 2001;
Delcroix et al., 2003; Malik-Hall et al., 2005), capsaicin,
electrical stimulation (Dai et al., 2002; Ji et al., 1999),
Freund’s adjuvant (Obata et al., 2003), and nerve transec-
tion (Obata et al., 2003).
MAPK p38 is activated in response to peripheral inflam-
mation (Ji et al., 2002), and activation of TRPV1 leads to
p38-dependent hyperalgesia (Mizushima et al., 2005). In-
flammation, axotomy, and spinal nerve ligation similarly
Neuron
Reviewactivate p38 in spinal cord and DRG neurons, contributing
to neuropathic pain (Jin et al., 2003; Kim et al., 2002). In the
spinal nerve ligation model of painful peripheral neuropa-
thy, TNFa was central to p38 phosphorylation and me-chanical hyperalgesia (Jin and Gereau, 2006; Pollock
et al., 2002; Schafers et al., 2003). But also receptor acti-
vation and retrograde transport of locally produced NGF
resulted in p38 activation leading to increased expression
of TRPV1 (Ji et al., 2002).
Additional members of the MAPK family, c-Jun amino-
terminal kinase 1 (JNK) and ERK5, are also implicated in
nociception. Nerve transection results in chronic activa-
tion of JNK in DRGs in a process that appears to require
retrograde transport (Kenney and Kocsis, 1998), and
TNFa induces activation of JNK in cultured sensory neu-
rons (Pollock et al., 2002).
Nitric Oxide (NO)
In addition to the kinases, reviewed above, the second
messenger nitric oxide (NO) contributes to induction of
pain and sensitization in humans (Holthusen and Arndt,
1994), rats (Aley et al., 1998; Chen and Levine, 1999), as
well as Aplysia (Lewin and Walters, 1999). The NO-pro-
ducing enzyme, nitric oxide synthase (NOS), was localized
immunohistochemically in small- and medium-diameter,
nociceptive DRG neurons in rat and monkey (Zhang
et al., 1993). NOS expression is prominent during develop-
ment and after nerve lesion (Majewski et al., 1995; Qian
et al., 1996). Its immunoreactivity is increased in DRG neu-
rons by noxious irritants (Vizzard et al., 1995, 1996) as well
as nerve injury (Choi et al., 1996; Steel et al., 1994; Zhang
et al., 1993). Also, production of the downstream effector
of NO, cGMP, sharply increases in response to exposure
to inflammatory mediators (Burgess et al., 1989a). In turn,
inhibition of NOS suppresses activity in dorsal roots orig-
inating from sciatic neuromas (Wiesenfeld-Hallin et al.,
1993) and reduces thermal hyperalgesia established by
chronic constriction injury or hindpaw inflammation
(Moore et al., 1993; Thomas et al., 1996). Also, in cultured
DRG neurons, the Prostaglandin E2 (PGE2)-induced
increase of TTX-R INa was partially suppressed by NOS
inhibitors (Aley et al., 1998).
However, unlike the other second messengers, NO has
the potential to induce opposing effects. Thus, antinoci-
ceptive effects of NO are also reported (Duarte et al.,
1992; Kawabata et al., 1994), potentially due to differential
dosing (Kawabata et al., 1994) or depth of injection into the
animals skin (Vivancos et al., 2003).
The exact function and interrelationship of the different
second messengers discussed above as well as others
(e.g., calcium influx, ceramide, caspases, BH4,.) in no-
ciceptor signaling remains to be established. Establish-
ment of these relationships must also take into account
the extent to which these signaling components are acti-
vated in the same cell and additionally whether they are
activated within the same or distinct cellular compart-
ments. Below, we expand upon these points in an effort
to highlight the importance of taking a broader cell-biolog-
ical approach to nociceptor signaling in order to under-
stand both the physiological and pathophysiological con-
sequences that can arise via the plethora of signaling
cascades potentially activated in response to noxious
stimuli.
Neuron 55, August 2, 2007 ª2007 Elsevier Inc. 367

for novel therapeutic interventions. But, illustrating the in- these important unanswered questions can be addressed
Neuronsufficiency of the current knowledge about nociceptive
signaling pathways, the important and very basic ques-
tion, which of these two complementary models can be
ruled out, has yet to be answered.
Model to Be Tested on the Level
of Signaling Cascades
At the level of the initial stimulus, noxious physical stimuli
and changes in the immediate tissue environment act on
the nociceptors. As reviewed by others (Julius and Bas-
baum, 2001; Scholz and Woolf, 2002), the concentration
of neurotransmitters, growth factors, hormones, fatty
acid derivates, neuropeptides, cytokines, ATP, and pro-
tons are altered, resulting in what has been referred to
as an inflammatory soup. As eachmediator has the poten-
tial to individually modulate sensitization, convergence at
the stimulus level seems unlikely. Also, evidence for con-
by studying the next level, the intracellular signaling.
There, to validate either of the two models, one has to fol-
low the so-far-identified signaling components all the way
down to the effector molecules. Doing this for more than
one cascade, it will emerge, if the cascades and/or effec-
tors are separate or not. Keeping markers for nociceptive
subtypes included, will indicate also the use of parallel
versus convergent neuronal subtypes.
Investigations to test the complementary models for
validity has to consider new aspects of importance
much beyond the classical signaling components dis-
cussed so far, which are established by recently emerging
results discussed in the following sections.
Variability of Receptor Signal-Cascade Coupling
In other cellular systems, it is known that stimuli which lead
to similar net effects often activate the same intracellularA Cell-Biological View of Nociceptor Signaling
Parallel versus Convergent Signaling
The studies reviewed above have established the involve-
ment of selected classical signaling molecules in sensiti-
zation of primary afferent nociceptors (Figure 1). But
even with a fairly solid understanding of the contribution
of a number of signaling components a synthesis of the
pathways mediating sensitization is lacking. Having
many stimuli all leading to sensitization, a priori two com-
plementary models of signaling have to be considered: (1)
the signals resulting in nociceptor sensitization are sepa-
rate and involve distinct and nonoverlapping signaling
components which modify separate effector molecules
(Figure 2, left). (2) The signal cascades are not separate,
i.e., the initiated cascades converge (partially or com-
pletely) (Figure 2, right). Both of these models bear impor-
tant implications. If the signaling is parallel, the current
phenotypic distinction between mechanical and thermal
hyperalgesia would have to be further differentiated, as
necessarily the involvement of distinct effector molecules
defines also mechanistically distinct phenotypes. On the
other hand, if convergence occurs, a common ‘‘nocicep-
tion module’’ would be defined with intriguing possibilitiesvergence at the receptor level has, so far, not emerged, as
a wide variety of receptors from classes as different as G
protein-coupled receptors, receptor tyrosine kinases,
368 Neuron 55, August 2, 2007 ª2007 Elsevier Inc.TNF-family receptors, ligand-gated ion channels, and
cytoplasmic/nuclear steroid hormone receptors are
activated (Figure 2).
But the models have to be tested on two successive
levels of signal transmission: the use of distinct versus
convergent neuronal subpopulations and of distinct
versus convergent intracellular signaling pathways. Po-
tentially, separate stimuli can act on separate neurons,
as, e.g., the respective receptors are not expressed ubiq-
uitously. And, indeed, nociceptive neurons of varying sub-
types are differentiated by histological, electrophysiologi-
cal, and molecular characteristics (Julius and Basbaum,
2001). How these neurons are interconnected, how other
neurons such as the peripheral sympathetic nervous sys-
tem and central interneurons modulate them, as well as to
what extent they innervate the same or distinct areas in the
spinal cord is beyond the scope of this review. We would
only like to note here, that while the number of nociceptive
neuron subtypes is increasing, most nociceptors are, nev-
ertheless, described as polymodal, i.e., responding to
multiple kinds of stimuli (Lewin and Moshourab, 2004).
Therefore, the question of parallel versus convergent use
of nociceptive neuron subtypes remains open. Some of
Figure 2. Parallel versus Convergent
Signaling Models
The observed multitude of signaling pathways,
all of which lead to the induction of hyperalge-
sia, raises the question of the relationships
between the signaling cascades. Two comple-
mentary models have to be considered: (1) the
signaling components define parallel path-
ways, leading to the modification of distinct ef-
fector molecules (orange arrows, red ovals,
left). Alternatively, (2) at least partial con-
vergence occurs, leading necessarily to the
formation of a nociceptive module (orange
arrows, red area, right). Currently, data do not
falsify any of the two. Detailed analysis of the
signaling pathways, their downstream targets,
as well as modulatory sites in the primary affer-
ent nociceptive neuron is required.
Reviewsignaling cascades (e.g., receptor tyrosine kinases in Dro-
sophila eye development [Freeman, 1996]). In nociceptive
neurons, do extracellular mediators, which activate the

same class of receptors, share their intracellular signaling
mechanism? Both epinephrine and PGE2 use as-coupled
G protein receptors (GPCRs). However, while epinephrine
hyperalgesia involves PKA, PKC3, and ERK1/2, PGE2-
induced hyperalgesia is PKA dependent only (Aley et al.,
2001; Hucho et al., 2005; Khasar et al., 1999a). Therefore,
stimulating a similar receptor/mediator module such as
GPCRs coupled to as does not necessarily result in the
stimulation of the same downstream events. Core compo-
nents such as PKC3 and ERK1/2 can be excluded from
the sensitization process even though in both cases as is
activated.
Selective Activation of Signaling Pathways
At the moment, it remains unclear what determines the
use of the varying signaling pathways in nociceptive neu-
rons. Increasingly, the importance of subcellular cluster-
ing and signaling ‘‘hub’’ formation is being investigated.
One such class of compartments are lipid rafts. They are
membrane patches enriched in sphingomyelin- and cho-
lesterol-based lipids, accumulating a large number of pro-
teins (Ostrom and Insel, 2004). Functional consequences
of this subcellular localization have been assumed, as in
response to activation protein relocalization toward or
away from lipid rafts has been observed, and a variety of
signaling events is abolished if lipid rafts are disrupted.
Also, in nociception, lipid rafts are important. In behavioral
experiments, interferencewith fibronectin-integrin binding
attenuated PKC3-mediated hyperalgesia. In contrast,
PKA-mediated sensitization can be abolished by interfer-
ence with laminin-integrin binding (Dina et al., 2005). While
the latter effect is dependent on the integrity of lipid rafts,
the former is not. And indeed, reflecting these in vivo ob-
servations, biochemically only the laminin-binding integrin
a1 is found to be localized to lipid rafts in DRG neurons,
while the fibronectin-binding a5 integrin is not (Dina
et al., 2005). Other receptors involved in nociception
such as the b2-adrenergic receptor, the bradykinin recep-
tor 2 (deWeerd and Leeb-Lundberg, 1997), and the neuro-
kinin receptor 1 (Monastyrskaya et al., 2005) have been
found to be localized to membrane subdomains in non-
neuronal cells. Whether they compartmentalize to lipid
rafts also in nociceptive neurons and whether localization
of these receptors is relevant to nociceptor function
awaits further investigation.
The ‘‘Primed State’’: A New Mode of Sensitization
Two functional modes have been well described in noci-
ceptors: the naive or normal mode and the sensitized or
hyperalgesic mode. Recent work on PKC-dependent hy-
peralgesia suggests that there is an additional complexity
to consider, a mode referred to as the ‘‘primed state’’ (Fig-
ure 3; Aley et al., 2000). In the primed state, basal nocicep-
tive thresholds are still normal (Parada et al., 2003a). In-
stead of being sensitized against physical stimuli, the
nerve is sensitized against exposure to sensitizing agents.
Neuron
ReviewIn this primed state, far lower concentrations of inflamma-
tory mediators are sufficient to elicit enhanced and nota-
blymuch prolonged hyperalgesia. In contrast to traditional
sensitization induced by inflammatory mediators, whichrecovers within minutes to hours, neurons can remain in
the primed state for several weeks. Both the establish-
ment, which does not require prior hyperalgesia, and
maintenance of the primed state is PKC3 dependent
(Aley et al., 2000; Parada et al., 2003b). Inhibition or down-
regulation of PKC3 in rats five days after the establishment
of the primed state results in return to the initial nonprimed
state (Parada et al., 2003b). Given the long-lasting effects
of priming, this state could potentially underlie the chron-
ification of pain. Consistent with this idea, PKC3 also plays
a central role in models of chronic pain (Dina et al., 2000,
2001b; Joseph and Levine, 2003a, 2003b).
Plasticity of Signaling Cascades
Investigating the primed state not only shows the plasticity
of nociceptive neurons beyond the naive/sensitized di-
chotomy (see above) but also exemplifies the plasticity
in signaling pathways in response to the same stimulus.
PGE2-induced hyperalgesia in naive animals is mediated
by PKA. However, switching the nociceptive neuron
from the naive to the primed state leads to a shift in the un-
derlying signaling cascade. In the primed nociceptor,
PGE2 hyperalgesia is additionally mediated by PKC3
(Aley et al., 2000). While the mechanism underlying the
switch is unknown, the site of this switch nevertheless
has been narrowed down to a site downstream of adenylyl
cyclase activity but upstream of PKA activation (Parada
et al., 2005). This is surprising, as cAMP signaling is often
considered to be synonymous with PKA activity. Obvi-
ously, one component of a cascade should not be taken
Figure 3. Three Modes of Sensitivity
Three neuronal states can be differentiated in the nociceptive neuron,
the naive, the just recently identified primed, and the hyperalgesic
state. (A) Exposure of the naive neuron to noxious physical or inflam-
matory stimuli (bold capital S) results in hyperalgesia (red area, B)
i.e., sensitization of the nerve toward future physical stimuli. Depen-
dent on the animal model the hyperalgesic state lasts for some few
hours. While the sensitivity to physical stimuli then returns to normal,
the sensitivity to successive inflammatory stimuli (small s, E) remains
increased. The primary afferent nociceptor remains in the primed state
(C). This state can be established also by treatment with small concen-
trations of inflammatory mediators (small s), which do not result in hy-
peralgesia (D, dotted line). In contrast to the hyperalgesic state, the
primed state is still present weeks later. The hyperalgesia induced in
the primed state is markedly prolonged (F). The establishment as
well as the maintenance of the primed state is PKC3-dependent. If in
the primed neuron PKC3 is blocked (G) the neuron returns to the naive
state (H).to indicate involvement of the whole cascade, even if the
components can directly interact with each as do cAMP
and PKA. While switches of signaling pathways have
been described in other cellular systems (e.g., the switch
Neuron 55, August 2, 2007 ª2007 Elsevier Inc. 369