Neuroscience and Biobehavioral Reviews 33 (2009) 784792

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Contribution of the activation of satellite glia in sensory ganglia to

pathological pain
Mamoru Takeda *, Masayuki Takahashi, Shigeji Matsumoto
Department of Physiology, School of Life Dentistry at Tokyo, Nippon Dental University, 1-9-20, Fujimi-cho, Chiyoda-ku, 102-8159 Tokyo, Japan

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 9 November 2008
Received in revised form 24 December 2008
Accepted 26 December 2008

Peripheral tissue injury/inammation can alter the properties of somatic sensory pathways, resulting in
behavioral hypersensitivity and pathological and/or chronic pain, including increased responses to pain
caused by both noxious stimuli (hyperalgesia) and normally innocuous stimuli (allodynia). Although
there are increasing reports that glia in the spinal cord contribute to the maintenance of pathological
pain, recent evidence suggests that activation of satellite glia in sensory ganglia may also play an
important role in the development of hyperalgesia and allodynia. There is evidence that non-synaptically
released chemical mediators derived from both neurons and satellite glia may trigger chronic pain via
autocrine and/or paracrine mechanisms and that augmented excitability of primary afferent neurons
results in changes in central pain-signaling neurons (central sensitization). The focus of the present
review is on the contribution of the activation of satellite glia in sensory ganglia to pathological pain. In
addition, we discuss potential therapeutic targets in satellite glianeuronal interactions for the
prevention of pathological pain.
2009 Elsevier Ltd. All rights reserved.

Keywords:
Allodynia
Hyperalgesia
Paracrine
Proinammatory cytokine
Satellite glia
Sensory ganglia

Contents
1.
2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Functional basis for sensory ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Overview of sensory ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Cross-communication within sensory ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathological pain and glial activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Candidates for the activation of satellite glia in sensory ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Contribution of neuronSGC communication to hyperalgesia and allodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Functional signicance of activation of SGCs in pathological pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Amplication of nociceptive sensory signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Therapeutic targets for pathological pain: sensory ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Pain is divided into two groups: physiological pain (nociceptive
pain) and pathological pain. Physiological pain is adaptive,
transient, and has a protective role as a warning signal of potential
tissue damage in response to a noxious stimulus (Cao and Zhang,

* Corresponding author. Tel.: +81 3 3261 8740; fax: +81 3 3261 8740.
E-mail address: m-takeda@tokyo.ndu.ac.jp (M. Takeda).
0149-7634/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2008.12.005

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2008). Conversely, pathological clinical pain is usually maladaptive, persists, and serves no meaningful defensive or other helpful
purpose (Sholtz and Woolf, 2002; Cao and Zhang, 2008). Generally,
peripheral tissue injury and inammation can alter the properties
of somatic sensory pathways, resulting in behavioral hypersensitivity and increased responses to pain caused by both noxious
stimuli (hyperalgesia) and normally innocuous stimuli (allodynia)
(Merskey and Bogduk, 1994; Sholtz and Woolf, 2002). Since it was
reported that peripheral inammation or injury induces the
release of neurotransmitters from central terminals (Garry and

M. Takeda et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 784792

Hargreaves, 1992; Bereiter and Benetti, 1996; Carleson et al., 1996)

and increases the excitability of neurons in the dorsal horn of the
spinal cord, sensitization of the central nervous system (CNS) has
been thought to contribute to inammation- or injury-induced
hyperalgesia (Dubner and Ruda, 1992; Coderre et al., 1993; Ren
et al., 1994). The appearance of such a hyperalgesia leads to suggest
that changes in the excitability of primary afferents (peripheral
sensitization) and/or altered information processing in the spinal
cord or higher centers are related to enhanced pain sensation
(Millan, 1999; Sholtz and Woolf, 2002). Neurons generally use
neurotransmitters released from vesicles at presynaptic terminals
to communicate with other cells (Stevens, 2003). However, recent
studies have demonstrated that non-synaptically released diffusible chemical messengers, such as ATP, substance P (SP),
calcitonin gene-related peptide (CGRP), and GABA, may modify
the somatic excitability of neurons in the sensory ganglia (Amir
and Devor, 1996, 2000; Takeda et al., 2005a,b; Hayasaki et al.,
2006; Zhang et al., 2007; Jing et al., 2008). For example, the release
of SP from trigeminal ganglion (TRG) neurons increases predominantly after peripheral inammation, indicating that local
paracrine mechanisms in the sensory ganglia contribute to the
development of inammation-induced sensory abnormalities
(Matsuka et al., 2001; Takeda et al., 2005a,b).
There is strong evidence that activation of glia (astroglia and
microglia) within the dorsal horn of the spinal cord and the
subsequent production of cytokines, such as interleukin (IL)-1b
and tumor necrosis factor a (TNFa), play an important role in the
creation and maintenance of pathological pain (Watkins et al.,
1997, 2001; Watkins and Maier, 2001). Indeed, behavioral
hyperalgesia following peripheral inammation is attenuated by
the administration of glial metabolic inhibitors, cytokine or nitric
oxide (NO) inhibitors (Watkins and Maier, 2001), suggesting that
spinal glial cells may contribute to the development of hyperalgesia. These pathological effects may not be limited to glial cells
within the CNS. Sensory ganglia in the CNS contain satellite glial
cells (SGCs) as well as astroglia in the CNS (Fig. 1), Anatomically,
the SGCs form a distinct sheath around nearly all individual
sensory neurons in the dorsal root ganglion (DRG) and are
associated with the transport and metabolism of various
molecules, such as glutamate and glucose (Hanani, 2005), and
maintain ionic homeostasis, including extracellular potassium
(Orkand et al., 1966; Newman et al., 1984; Vit et al., 2008). Recent
studies have demonstrated the importance of SGCs in modulating

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the function of sensory transmission, including nociception

(Stephenson and Byers, 1995; Cherkas et al., 2004; Hanani,
2005; Takeda et al., 2007, 2008a,b). Indeed, following inammation of peripheral tissues, SGCs begin to exhibit increased
expression of glial brillary acidic protein (GFAP) and IL-1b
(Takeda et al., 2007). It has also been reported that administration
of IL-1b enhances the excitability of nociceptive TRG neurons
following inammation, demonstrating the mechanism underlying inammatory hyperalgesia (Takeda et al., 2007).
The focus of the present review is on the modulation of
neuronal signals as a result of cross-talk between SGCs and
neurons in the sensory ganglia, particularly with regard to
pathological pain. We also introduce recent data and discuss
potential therapeutic targets for the prevention of pathological
pain.
2. Functional basis for sensory ganglia
2.1. Overview of sensory ganglia
Sensory ganglia, such as the DRG, TRG, and nodose ganglion
(NG), contain the cell bodies of primary afferent neurons, which
transmit sensory information from the periphery to the CNS
(Matthews and Cuello, 1982; Aldskogius et al., 1986). The
peripheral branches of TRG axons extend into the periphery and
form sensory endings in the skin, muscles, viscera, joints, and other
organs; the central branches enter the spinal dorsal horn and the
trigeminal spinal nucleus. In addition, sensory ganglia contain
SGCs that completely envelope the sensory neurons (Pannese,
1981; Pannese et al., 2003). In contrast with the large amount of
information available regarding glial cells in the CNS, little is
known about SGCs in the sensory ganglia. Morphologically, SGCs
are laminar and have no processes, unlike CNS astroglia (Hanani,
2005). In general, each sensory neuron has its own SGC and, thus,
the neurons and their surrounding SGCs form a morphologically
distinct functional unit (Hanani, 2005). Like other glial cells, such
as Schwann cells and astrocytes, SGCs have numerous receptors for
neurotransmitters and other bioactive molecules (Kettenmann
and Steinhauser, 2005; Hanani, 2005). It can be argued that SGCs
are analogous to astrocytes, because both cell types are closely
related to neuronal somata, carry for neurotransmitters, and
regulate the concentration of ions in the extracellular space
(Hanani, 2005). Thus, it is possible that the cross-talk within
sensory ganglia (neuronsneurons, neuronsSGCs, and SGCs
SGCs) serves as a site for the modication of neuronal signals in
the sensory pathway (Figs. 1 and 2A).
2.2. Cross-communication within sensory ganglia

Fig. 1. Schematic drawing of the neural pathway for the transmission of nociceptive
signals from primary afferent neurons, via the supercial lamina in the dorsal horn
of spinal cord, to the central nervous system. Note that primary sensory neuronal
glial cells (satellite glia) play an important role in the modulation of sensory signals,
as do secondary sensory neuronal glia (spinal glia).

It has been found that autonomic ganglia, such as the

sympathetic and parasympathetic ganglia, have dendrites and
chemical synapses, which are absent in sensory ganglia. Although
primary afferent neurons are generally thought to constitute
independent sensory communication channels, Devor and Wall
(1990) demonstrated cross-excitation in the DRG in nerve-injured
and intact rats. As shown in Fig. 2A, Devor and Wall (1990) found
that most DRG neurons are transiently depolarized when the axons
of neighboring neurons in the same ganglion are stimulated
repeatedly (cross-excitation), and suggested that activitydependent changes in the extracellular concentration of K+ and
the non-synaptic release of transmitters may mediate mutual
depolarization among DRG neurons. Previously, Matsuka et al.
(2001) reported evidence that TRG neurons release ATP and SP
concurrently in vivo. Oh and Weinreich (2001) also observed that
in terms of the cross-excitation of the soma of NG neurons, vagal
primary afferent neurons are qualitatively similar to DRG neurons.

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Fig. 2. Possible mechanism for the intraganglionic modulation of sensory signals.

(A) Neuronneuron communication. Activated neurons release K+ ions and
neurotransmitters into the extracellular space within the sensory ganglia. The
elevated potassium concentration depolarizes the neighboring neurons and/or
neurotransmitters (e.g. ATP, substance P) activate neighboring neurons via specic
receptors. (B) Neuronglial communication. Activated neurons release
neurotransmitters into the extracellular space within the sensory ganglia. The
neurotransmitters released, such as calcitonin gene-related peptide, substance P,
and ATP, also activate satellite glia via specic receptors. Activated satellite glial
cells release cytokines, such as interleukin (IL)-1b and tumor necrosis factor a
(TNFa), which may further potentiate neuronal excitability. RAMP1, receptor
activity modifying protein 1; NK1R, NK1 receptor; P2X7R, P2X7 receptor.

Thus, it can be assumed that this sort of cross-talk is a general

physiological property of mammalian primary sensory neurons,
including sensory afferents (Fig. 2A). The cell bodies of primary
afferent neurons (which convey sensory signals from the periphery
to the CNS) are completely surrounded by several SGCs, forming
distinct functional units. Morphological studies have shown that
attening processes from glial cells lie in close proximity to the
plasma membrane of neuronal cells. It is now accepted that glial
cells, which outnumber neuronal cells (e.g. 10:1 in the TRG),
directly inuence neuronal activity by controlling the microenvironment in the ganglion (Pannese et al., 2003; Hanani, 2005). A
major determinant of neuronal excitability is the extracellular
concentration of K+ (Haydon, 2001), which is regulated primarily
by ion channels expressed by the SGCs (Hanani, 2005) that
surround primary sensory neurons. It is known that SGCs have
marked K+ permeability (Hosli et al., 1978) and trigeminal SGCs
show mainly inward K+ conductance (Cherkas et al., 2004). The
conventional model of neuronal ion balance predicts that the
ability of SGCs to maintain normal extracellular K+ concentrations
would be associated with altered excitability of primary sensory
neurons (Laming et al., 2000; Wlz, 2000). More recently, Vit et al.
(2008) demonstrated the importance of SGCs in regulating the

extracellular K+ concentration between neurons and SGCs, and

suggested that changes in this balance may lead to neuropathic
pain.
Although there is evidence that some chemical signals, such as
SP and CGRP, affect SGC function under normal conditions
(Matsuka et al., 2001; Wienrich and Kettermann, 2004; Jing
et al., 2008; Li et al., 2008), little is known about the chemical
messengers derived from sensory neurons that affect the excitability of SGCs. Recently, Zhang et al. (2007) reported that electrical
stimulation of DRG neurons elicits robust vesicular ATP release
from the somata and that the rate of release events increases with
the frequency of nerve stimulation; external Ca2+ entry is required
for release. In addition, the ATP released activates P2X7 receptors in
the SGCs that envelope each DRG neuron and triggers communication between the neuronal soma and glial cells. Since it has
been reported that CGRP increases the release of cytokine (e.g.,
TNF-a) from SGCs and the expression of inducible NOS (iNOS) as
well as production of NO in the trigeminal ganglia (Thalakoti et al.,
2007; Li et al., 2008), paracrine signalings via CGRP play an
important role in the cross-excitation between neuron and SGCs.
Thus, it can be concluded that the somata of sensory neurons
release transmitters actively and play a crucial role in the
bidirectional communication between neurons and their surrounding SGCs (Takeda et al., 2007; Zhang et al., 2007; Thalakoti
et al., 2007; Li et al., 2008 Fig. 2B).
Furthermore, glial cells in most regions of the CNS are coupled
by gap junctions, which allow the passage of ions and small
molecules (Rouach et al., 2002; Rozental et al., 2002). Because the
degree of dye-coupling changes in pathological conditions
(Cherkas et al., 2004), it can be assumed that the physiological
importance of the gap junctions is to allow the rapid redistribution
of K+ and other ions in adjacent SGCs (Huang et al., 2005) to
maintain the highly negative intracellular potential. Gap junctions
also permit the passage of Ca2+ and are a means by which Ca2+
waves are initiated in adjacent astrocytes (Vit et al., 2006).
3. Pathological pain and glial activation
3.1. Candidates for the activation of satellite glia in sensory ganglia
Peripheral tissue injury and inammation result in immune
activation, and the release of host neuroactive substances to
peripheral terminals of sensory neurons or along the length of the
degenerating bers (Cao and Zhang, 2008). These events have a
direct effect on the electrical activity of injured and intact axons.
Alternatively, such neuroactive substances may serve as retrogradely transported signals to inuence gene activation in the
soma of sensory ganglia, leading to hyperexcitability in spinal
dorsal horn neurons. Several inammatory mediators (bradykinin,
SP, CGRP), cytokines (IL-1b, TNFa), chemokines (monocyte
chemoattractant protein-1: MCP-1), and neurotrophic factors
(nerve growth factor, brain-derived neurotrophic factor (BDNF),
and glial cell line-derived neurotrophic factor (GDNF)), as well as
prostaglandin E2 (PGE2), ATP, and NO among others, are thought to
play central roles in inammatory hyperalgesia at the site of
inammation (Sholtz and Woolf, 2002; Julius and McCleskey,
2005; MacMahon et al., 2005). However, the actions of these
inammatory mediators are not limited to the peripheral site of
inammation and they may effectively alter signaling between
neurons and glial cells. Although several factors (CGRP, ATP, BDNF,
TNFa, and IL-1b) and their receptors have been found in SGCs
(Wetmore and Olson, 1995; Weick et al., 2003; Ohtori et al., 2004;
Li et al., 2005; Zhang et al., 2007; Hatashita et al., 2008; Jing et al.,
2008), it is not clear which factors activate satellite glia in
pathological pain states, how SGCs produce pain, and which
mediators are involved. On the basis of existing evidence, the

M. Takeda et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 784792

possible mechanisms underlying SGC activation and the subsequent hypersensitivity to pain are discussed in the following
section.
3.2. Contribution of neuronSGC communication to hyperalgesia and
allodynia
It has been reported recently that spinal cord microglia and
astrocytes are responsible for the creation of an exaggerated
pathological state of pain (Watkins et al., 1997; Watkins and Maier,
2001). Recent studies have demonstrated that the importance of
SGCs lies in their ability to modulate sensory transmission,
including nociception (Stephenson and Byers, 1995; Cherkas
et al., 2004; Hanani, 2005; Dublin and Hanani, 2007; Takeda
et al., 2007, 2008b). Indeed, Stephenson and Byers (1995)
discovered increased levels of glial brillary acidic protein (GFAP)

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in SGCs of the TRG following tooth pulp injury. GFAP is a marker of

both glial cells and CNS astrocytes. Following inammation, glial
cells are activated and produce proinammatory cytokines, such as
IL-1b (Watkins et al., 2001; Li et al., 2005; Takeda et al., 2007). In a
model of trigeminal neuropathic pain, axotomy elicited changes in
neurons and SGCs of the TRG (Cherkas et al., 2004; Chudler et al.,
1997). Vit et al. (2008) have found that changes in the expression of
glia-specic inward rectifying K+ (Kir 4.1) channels in SGCs
contributes to the neuropathic pain. A recent study also demonstrated that injection of NO/protons in the temporomandibular
joint (TMJ) leads to activation of TRG neurons and increased
expression of mitogen activated protein kinases (MAPs) in the
SGCs (Freeman et al., 2008). The MAP signaling cascade is known to
play an important role in the initiation and maintenance of
inammatory pain (Sagar and Krebs, 1995; Ji, 2004). Together,
these data suggest that activation of SGCs within the TRG may

Fig. 3. Activation of satellite glia and satellite glial interleukin (IL)-1b paracrine mechanisms potentiate neuronal excitability following inammation. (A) There was an
increase in the percentage of trigeminal ganglion (TRG) neurons encircled by glial brillary acidic protein (GFAP)- and IL-1b-immunoreactive (IR) satellite glial cells after
inammation. Data show the mean percentage of neurons encircled by GFAP- and IL-1b-immunoreactive satellite glial cells. *P < 0.05 for control vs inamed rats. (B) GFAPand IL-1b-immunoreactivity was coexpressed in the same cells in inamed rats. Bar = 20 mm. (C) Differences in the expression of IL-1 receptor type I-immunoreactive (IL1RI-IR) TRG neurons innervating the facial skin in control and inamed rats. Inset, triangles show IL-1RI-IR TRG neurons. Size frequency distribution of IL-1RI-IR TRG neurons
innervating the facial skin in control and inamed rats. (D) Occurrence of IL-1b-induced membrane depolarization in small-diameter TRG neurons innervating the facial skin
in normal and inamed rats. Size distribution of TRG neurons responsive to IL-1b (1 nM) in both control and inamed rats. (E) Typical example of small-diameter TRG neurons
in inamed rats; application of 10 nM IL-1b induced strong depolarization associated with spike discharges.

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M. Takeda et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 784792

trigger enhanced neuronal excitability following trigeminal nerve

injury and inammation, which is associated with hyperalgesia
(abnormally intense pain elicited by noxious stimuli).
Recently, we investigated the basis for both mechanical
hyperalgesia and changes in the sensitivity of neurons following
peripheral inammation using the patch-clamp technique combined with immunohistochemistry (Takeda et al., 2007, 2008b;
Fig. 3). We found that (i) in rats with peripheral inammation,
most TRG neurons were encircled by GFAP- and IL-1b-immunoreactive cells, which differed signicantly from the picture in
control rats (Fig. 3A, B); (ii) inammation upregulated the
expression of the IL-1 type I receptor (IL-1RI) in small-diameter
TRG neurons innervating the facial skin (Fig. 3C); and (iii)
inammation potentiated the excitability of acutely dissociated
small-diameter (Ad and C type) TRG neurons innervating the facial
skin (Fig. 3D, E) by suppressing voltage-gated potassium currents
(Takeda et al., 2007, 2008a). Next, we examined the effects of
inammation on the excitability of nociceptive Ad TRG neurons
innervating the inamed tissues in vivo, and investigated whether
changes in neuronal excitability involved a cytokine paracrine
mechanism (Takeda et al., 2008a). We found that the number of Ad
TRG neurons ring spontaneously, as well as the rate of ring, was
signicantly greater in rats with peripheral inammation than in
control rats (Fig. 4A). In addition, in both control rats and rats with
peripheral inammation, the spontaneous ring rate of Ad TRG
neurons was decreased in a current-dependent manner following
the local microiontophoretic application of an IL-1RI antagonist,
but increased after the iontophoretic application of IL-1b (Fig. 4B).
The IL-1RI antagonist also inhibited Ad TRG neuron activity evoked
by mechanical stimulation in rats with peripheral inammation
(Fig. 4C). Finally, the mechanical threshold of nociceptive TRG

neurons was signicantly lower in rats with peripheral inammation compared with control rats but, after the application of the IL1RI antagonist, this signicant difference no longer existed
(Fig. 4C). Taken together, these data suggest that activation of
SGCs modulates the excitability of nociceptive TRG neurons via an
IL-1b paracrine mechanism following inammation and that the
upregulation of IL1-RI in the soma may be a part of the mechanism
underlying inammatory hyperalgesia (Takeda et al., 2007,
2008b).
The precise mechanism underlying the mechanical hyperalgesia associated with glial cellneuronal cross-talk after inammation remains to be determined; however, it is likely to involve the
increased excitability of nociceptive Ad TRG neurons, which occurs
as a result of the activation of satellite glia. As shown in Fig. 4, we
propose that the increase in the excitability of nociceptive Ad TRG
neurons innervating the inamed facial skin is the mechanism
underlying inammatory hyperalgesia. Under normal conditions,
when noxious mechanical stimulation is applied to the skin, highthreshold mechanoreceptors are activated, generating an action
potential that is subsequently conveyed through secondary
neurons in the spinal cord to the sensory cortex (physiological
nociceptive pain; Fig. 5A). Conversely, under inamed conditions,
peripheral inammation activates nociceptive primary afferents,
resulting in the release of pain-associated substances, such as SP
and ATP (Watkins and Maier, 2001; Watkins et al., 2001), in both
central and peripheral nerve terminals. Recently, we reported that
TMJ inammation increases the fraction of small-diameter and SPimmunoreactive TMJ neurons (Ad and C type) and that SP release
may activate neighboring non-nociceptive Ab TRG neurons
innervating the facial skin, upregulating somal tachykinin NK1
receptors (Takeda et al., 2005a,b). Following tissue damage or

Fig. 4. Activation of interleukin (IL)-1b receptors of nociceptive sensory ganglion neurons via an IL-1b paracrine mechanism contributes to hyperalgesia. (A) Bar graph
showing that the percentage of Ad trigeminal ganglion (TRG) neurons exhibiting spontaneous ring increases signicantly after peripheral inammation (upper panel). The
lower panel shows differences in mean spontaneous discharges rates between control and inamed rats. (B) Inhibition of mean discharge frequency of Ad TRG neurons
following iontophoretic application of an IL-1 receptor antagonist in inamed rats. *P < 0.05 for control vs inamed rats; #P < 0.05 for before vs after application of 50 and
90 nA (5 min); NS, not signicant (control vs inamed + IL-1 receptor antagonist (90 nA, 5 min). (C) Increased Ad TRG neuronal activity evoked by noxious pinch stimulation
after inammation and effects of iontophoretic application of an IL-1 receptor antagonist on mean discharge frequency after noxious pinch stimulation. *P < 0.05 for
comparisons of mean mechanical response threshold between control and inamed rats, as well as comparisons of mean mechanical threshold before and after iontophoretic
application of the IL-1 receptor antagonist (90 nA, 5 min).

M. Takeda et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 784792

Fig. 5. Possible mechanism underlying inammatory hyperalgesia following

inammation and nerve injury. (A) Under normal conditions, when noxious
mechanical stimulation is applied to the skin, high-threshold mechanoreceptors
(nociceptive) are activated, generating an action potential. This action potential
discharge is subsequently conveyed through a secondary neuron in the spinal cord
to the sensory cortex (physiological nociceptive pain). (B) Under inamed
conditions, peripheral inammation activates the nociceptive primary afferents
and, as a result, promotes the release of pain-associated substances, such as
substance P (SP), in the soma of trigeminal ganglion (TRG) neurons. Peripheral
inammation upregulates NK1 receptor expression in satellite glial cells and SP
stimulates the production of interleukin (IL)-1b in glial cells. This may potentiate
the synthesis and/or release of IL-1b via paracrine mechanisms in satellite glial
cells. It is therefore possible that IL-1b suppresses voltage-gated potassium
currents in TRG neurons via protein kinase C/G-protein-coupled signaling pathways
and that this contributes to the potentiation of the neuronal excitability of TRG
neurons innervating the inamed tissue. It can be assumed that the amplied
discharge frequency of Ad TRG neurons contributes to the sensitization of
secondary neurons and the development of hyperalgesia.

inammation, spinal glial cells are activated to release inammatory mediators, such as prostaglandins and IL-1b (Watkins et al.,
1997; Hashizume et al., 2000; Shi et al., 2006), and express NK1
receptors, which have a high afnity for SP (Marriott, 2004). We did
not examine whether peripheral inammation upregulates NK1
receptor expression in SGCs, although others have shown that SP
stimulates IL-1 production in cultured glial cells (Martin et al.,
1992, 1993). In addition, there is a report that NK1 receptor
activation depolarizes the membrane potential in astrocytes
(Wienrich and Kettermann, 2004). Indeed, we found that SGCs
in the TRGs coexpressed GFAP and IL-1b, and that this expression
was higher in rats with peripheral inammation than in control
rats (Takeda et al., 2007). These data suggest that peripheral
inammation can depolarize trigeminal SGCs via activation of NK1
receptors (SP release from small TRG neurons). This may potentiate
the synthesis and/or release of IL-1b via a paracrine mechanism in
the SGCs, whereas development of mechanical allodynia due to SP
potentiates the excitability of Ab TRG neurons (Takeda et al.,
2005b). Liu et al. (2006) reported that, in the TRG neurons, the
potentiation of voltage-gated sodium currents by chronic application of IL-1b is suppressed in the presence of selective inhibitors of
protein kinase C/G-protein-coupled signaling pathways; consequently, it is possible that IL-1b suppresses voltage-gated
potassium currents in TRG neurons via similar pathways and that
this effect contributes to the potentiation of neuronal excitability

789

of TRG neurons innervating the inamed tissue. Under these

conditions, when noxious stimulation is applied to the inamed
skin, the higher-threshold mechanoreceptors (nociceptive Ad TRG
neurons) innervating inamed tissue are activated, generating
action potentials that are conveyed to the cell soma in TRG ganglia.
The discharge frequencies of nociceptive Ad TRG neurons are
augmented or amplied through an intraganglionic paracrine
mechanism that involves IL-1b (Takeda et al., 2008a). It is possible
that the amplied discharge frequency of Ad TRG neurons
facilitates the release of neurotransmitters from central terminals
in the trigeminal nucleus, which contributes to the sensitization of
secondary neurons and the development of hyperalgesia. In
support of this idea, complete Freunds adjuvant-induced inammation upregulated the number of IL-1b- and/or IL-1RI-immunoreactive neurons and glial cells in the DRG (Li et al., 2005).
Because IL-1b also induces the release of SP from cultured DRG
neurons through a prostanoid pathway (Inoue et al., 1999), we
assume that SP further activates IL-1b release from the SGCs,
leading to hyperalgesia.
Alternatively, it has been reported that axotomy and inammation induce profound changes that affect both neurons and glial
cells, resulting in greatly augmented coupling between SGCs
(Cherkas et al., 2004; Dublin and Hanani, 2007). Dublin and Hanani
(2007) reported that administration of a gap junction blocker
prevented the inammation-induced decrease in the pain threshold. Although the precise functional signicance of this phenomenon remains unknown, we can speculate that the increased
excitability of TRG neurons may lead to an increase in the
extracellular K+ concentration and that the augmented coupling
may enable the SGCs to redistribute K+ ions and other harmful
substances more effectively. Indeed, trigeminal SGCs are known to
show marked K+ permeability and express the glial-specic inward
rectifying K+ channel Kir 4.1 (Cherkas et al., 2004; Vit et al., 2006).
Specic silencing of Kir 4.1 using RNA interference leads to
spontaneous and evoked facial pain-like behavior in rats (Vit et al.,
2008). These results suggest that changes in the function of SGCs,
including gap junctions and Kir 4.1 channels, may be involved in
the production of chronic pathological pain.
More recent studies suggest that chemokines and chemokine
receptors contributes to the development and maintenance of
chronic pain (White et al., 2007). For example, chemokines and
their receptors are expressed in the sensory neurons as well as the
SGCs of the DRG, and those expressions are upregulated following
a ligation of the sciatic nerve or a compression of the lumber DRG
(Abbadie et al., 2003; Tanaka et al., 2004; White et al., 2005),
indicating that chemokines and chemokine receptors might play a
key role in generating the neuropathic pain. Indeed, activation of
chemokine receptors by MCP-1 enhances the excitability of
nociceptive DRG neurons seen after a chronic compression of DRG
(White et al., 2005; Sun et al., 2006). These results suggest that
chemokine signalings have emerged as a key candidates to
mediate a neuronsatellite glia interaction underlying chronic
pain.
4. Functional signicance of activation of SGCs in pathological
pain
4.1. Amplication of nociceptive sensory signals
With regard to the functional signicance of transganglionic
signal communication in pathological pain, we suggest the
following two points. First, nociceptive information conveyed by
small-diameter primary afferents generally terminates on the
supercial layers of the spinal dorsal horn and trigeminal spinal
nucleus and, at these sites, the signals are modied by the
descending inhibitory or facilitatory systems (neuronal networks

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M. Takeda et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 784792

that arise from the periaqueductal grey, nucleus raphe magnus,

and locus coeruleus; Gebhart and Randich, 1990; Millan, 1999;
Porreca et al., 2002; Gebhart, 2004). In contrast with sensory
transmission in the secondary neurons of the spinal dorsal horn,
nociceptive and non-nociceptive signals are conveyed to the
secondary neurons independently by small- and large-diameter
bers, respectively, at the level of the primary afferents. Thus, we
can speculate that transganglionic communication in the sensory
ganglia may allow for an interaction between different types of
sensory information and this interaction may trigger the development of dysesthesia or pathological pain (e.g. allodynia). Second,
it is generally believed that each relay station in the synaptic
transmission of sensory signals from peripheral tissues, as well as
from the CNS (ascending sensory pathway), works as a sensory
signal amplication or attenuation site. It is possible that sensory
signals are effectively amplied or attenuated downstream of the
ascending sensory pathway and then sent to higher centers (e.g.
the thalamus and sensory cortex). Therefore, we can speculate that
transganglionic communication is one mechanism by which
central sensitization can be triggered, accompanied by the
development of pathological pain.

effects may not be limited to CNS glial cells. A recent study

provided evidence that activation of sensory ganglionic SGCs
modulates the excitability of primary nociceptive neurons via an
IL-1b paracrine mechanism following peripheral inammation,
and that cytokine release may be one of the important factors
determining the magnitude of the inammatory hyperalgesia.
Thus, the IL-1b receptor and functional coupling of voltage-gated
potassium channels may be useful therapeutic targets in the
treatment of pathological pain. It can be assumed that during the
early stage of peripheral injury and/or inammation, inhibition of
peripheral neuronglial cell interactions will prevent the exaggerated pathological pain states due to CNS glial activation.
However, further studies are needed to provide support for this
assumption.

4.2. Therapeutic targets for pathological pain: sensory ganglia

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In conclusion, several advances have been made towards
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Acknowledgments
The authors work reported herein was study was supported by
a Grant-in-Aid for Scientic Research (C) from the Japanese Society
for the Promotion of Science (No. 15591980 and No. 17591953 to
MT).

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