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Advanced Drug Delivery Rev
Pathophysiology and treatment of pain in joint diseaseB
Hans-Georg Schaible a, Martin Schmelz b,*, Irmgard Tegeder c
a Institut fur Physiologie, Universitat Jena, Teichgraben 8, D-07740 Jena, Germanyb Institut fur Anasthesiologie Mannheim, Theodor Kutzer Ufer 1-3, Universitat Heidelberg, D-68167 Mannheim, Germany
c pharmacentrum frankfurt, Institut fur Klinische Pharmakologie/ZAFES, Klinikum der Johann Wolfgang
Goethe-Universitat Frankfurt am Main, Theodor Stern Kai 7, D-60590, Germany
Received 23 May 2005; accepted 30 January 2006
Available online 28 February 2006
Abstract
Deep somatic pain originating in joints and tendons is a major therapeutic challenge. Spontaneous pain and mechanical
hypersensitivity can develop as a consequence of sensitization of primary afferents directly involved in the inflammatory
process, but also following sensitization of neuronal processing in the spinal cord (central sensitization) or higher centres.
Inflammatory pain is linked to sensitization of sensory proteins at the nociceptive endings whereas pain originating from nerve
damage (neuropathic pain) has been linked to changes in axonal ion channels producing ectopic discharge in nociceptors as a
source of pain. New targets for analgesic therapy include sensory proteins at the nociceptive nerve endings such as the
activating TRPV and ASIC channels, but also inhibitory opioid and cannabinoid receptors. Therapeutic targets are also found
among the axonal channels that set membrane potential and modulate discharge frequency such as voltage sensitive sodium
channels and various potassium channels.
D 2006 Elsevier B.V. All rights reserved.
Keywords: Opioids; Prostaglandin; TRPV; CB; ASIC; Sensitization; Hypersensitivity; Nociception
Contents
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1. Peripheral pain system—primary afferent nociceptors . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Peripheral sensitization—local inflammatory changes . . . . . . . . . . . . . . . . . . . . .
1.2. Molecular mechanisms of nociceptor activation and sensitization . . . . . . . . . . . . . . .
1.3. Neuropathic pain—neuronal injury along the peripheral nerve . . . . . . . . . . . . . . . .
2. Central pain pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Central sensitization—increased sensitivity in the central nervous system . . . . . . . . . .
0169-409X/$ - s
doi:10.1016/j.ad
B This review
* Correspondi
E-mail addr
iews 58 (2006) 323–342
ee front matter D 2006 Elsevier B.V. All rights reserved.
dr.2006.01.011
is part of the Advanced Drug Delivery Reviews theme issue on bDrug Delivery in Degenerative Joint DiseaseQ, Vol. 58/2, 2006.ng author. Tel.: +49 621 383 5015; fax: +49 621 383 1463.
ess: martin.schmelz@anaes.ma.uni-heidelberg.de (M. Schmelz).
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H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342324
2.2. Molecular mechanisms of spinal sensitization . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Nociceptive versus neuropathic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Advances in pain therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Targeting prostaglandins: cyclooxygenases, prostaglandin synthases and receptors . . . . . .
3.1.1. NO-NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2. LOX-COX inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Anti-inflammatory and peripheral analgesic efficacy of opioids and cannabinoids. . . . . . .
3.2.1. Opioids (central effects reviewed in chapter of Steinmeyer and Kontinnen) . . . . .
3.2.2. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Nuclear factor kappa B (NF-nB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Anti-IL-1 and anti-TNFa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Potential novel targets for pain treatment in arthritis . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Acid sensing ion channels (ASICs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Tetrodotoxin resistant voltage gated sodium channels (TTX resistant VGSCs) . . . . . . . .
4.3. Transient receptor potential (TRP) channels . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Bradykinin receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 333References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
1. Peripheral pain system—primary afferent
nociceptors
The nociceptive system consists of nociceptors in
the peripheral nerve and of nociceptive neurons in the
central nervous system. Nociceptors are thinly
myelinated Ay and unmyelinated C fibres whose
sensory endings are so-called bfree nerve endingsQ,because they are not equipped with corpuscular
endorgans. Most of the nociceptors are polymodal,
responding to noxious mechanical stimuli (painful
pressure, squeezing or cutting the tissue), to noxious
thermal stimuli (heat or cold), and to chemical stimuli
(for review, see [1]). Nociceptors of joints either
respond to noxious mechanical stimulation of the
joint such as hitting or overrotating the joint or they
are silent nociceptors which do not respond to even
noxious mechanical stimulation of the normal joint
[2]. The transduction of noxious stimuli in nocicep-
tors is provided by numerous membrane ion channels
and receptors (see peripheral sensitization). Nocicep-
tors can also exert efferent functions in the tissue by
releasing neuropeptides (substance P, calcitonin gene-
related peptide (CGRP)) from their sensory endings.
Thereby they induce vasodilation, plasmaextravasa-
tion and other effects, e.g. attraction of macrophages
or degranulation of mast cells. The inflammation
produced by nociceptors is called neurogenic inflam-
mation [3,4].
1.1. Peripheral sensitization—local inflammatory
changes
In normal tissue nociceptors have high thresholds.
Polymodal nociceptors in normal tissue are only
activated by noxious mechanical stimuli (painful
pressure, squeezing the tissue), noxious thermal
stimuli (heat or cold), and noxious chemical stimuli,
but not by gentle mechanical and thermal stimuli.
During inflammation, polymodal nociceptors are
sensitized. The activation threshold of nociceptors is
lowered, and they are excited by gentle stimuli that do
not normally activate them. In addition, sensitized
nociceptors show increased responses to noxious
stimuli. While cutaneous nociceptors are in particular
sensitized to thermal stimuli, nociceptors in deep
somatic tissue such as joint and muscle show
pronounced sensitization to mechanical stimuli. A
sensitized polymodal nociceptor in the joint starts to
respond to movements in the working range or to
palpation of the joint, and a sensitized nociceptor in
the muscle is activated by moderate pressure [5]. In
addition to polymodal nociceptors peripheral nerves
contain so-called initially mechanoinsensitive (silent)
nociceptors. These neurons are not activated by
noxious mechanical and thermal stimuli as long as
the tissue is normal. However, when the tissue is
inflamed these silent nociceptors are sensitized, and
they start to respond to mechanical and thermal
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 325
stimuli [2,6]. This class of nociceptors is characterized
by a particular long lasting response to algogenic
chemicals [7,8] and has a crucial role in mediating
neurogenic inflammation in human [9]. Moreover,
mechanoinsensitive nociceptors play a major role in
initiating central sensitization [10] and have distinct
axonal biophysical characteristics separating them
from traditional polymodal nociceptors [11,12].
1.2. Molecular mechanisms of nociceptor activation
and sensitization
Recent years have witnessed considerable progress
in the understanding of molecular events that lead to
activation and sensitization of nociceptors. Among the
sensory channels transient receptor potential (TRP)
channels, acid sensing ion channels (ASICs), brady-
kinin (B1, B2), and prostaglandin (EP1, EP2)
receptors play a major role. Also axonal channels
such as voltage gated sodium channels, K+ channels
and Ca2+ channels can contribute to nociceptor
activation as they contribute to setting of the
membrane potential and modulate discharge behavior.
Possible therapeutic targets among these structures
will be discussed in chapter 8.4.
Recently receptors for neuropeptides have also
been identified in primary afferent neurons. Examples
are receptors for substance P (neurokinin 1 receptors),
and calcitonin gene-related peptide (CGRP receptors).
Interestingly, receptors for inhibitory peptides are also
expressed, e.g. receptors for opioids, somatostatin and
NPY [13,14]. Most of these receptors could be
autoreceptors because the neurons with the receptors
also synthesize the corresponding neuropeptide. It has
been proposed that the activity or threshold of a
neuron results from the balance between excitatory
and inhibitory compounds. For example, many
nociceptive neurons seem to be under the tonic
inhibitory influence of somatostatin because the
application of a somatostatin receptor antagonist
enhances activation of the neurons by stimuli
[15,16]. The expression of neuropeptides and their
receptors in the neurons can be increased under
inflammatory conditions: substance P, CGRP and
neurokinin 1 receptor are upregulated during inflam-
mation [2,17–19].
It is conceivable that changes in the expression of
ion channels and receptors may contribute to the
maintenance of chronic pain. Some of the changes
seem to be stimulated by neurotrophins such as nerve
growth factor. Neurotrophins are survival factors
during the development of the nervous system, but
during inflammation of the tissue, the level of nerve
growth factor (NGF) is substantially enhanced. By
acting on the tyrosine kinase A (trk A) receptors, NGF
increases the synthesis of substance P and CGRP in
the primary afferents. NGF may also act on mast cells
and thereby activate and sensitize sensory endings by
mast cell degranulation [20]. However, also the
inflammatory mediator PGE2 is able to cause an
upregulation of expression of neurokinin 1 receptor in
DRG neurons [21].
1.3. Neuropathic pain—neuronal injury along the
peripheral nerve
In healthy sensory nerve fibres action potentials
are generated in the sensory endings upon stimula-
tion of the receptive field. Impaired nerve fibres
often show pathological ectopic discharges which are
generated at the site of nerve injury or in the cell
body of impaired fibres in dorsal root ganglia [22].
Ectopic discharges do not only occur in Ay- and C-
fibres but also in thick myelinated Ah-nerve fibres
that encode innocuous mechanosensory information.
Ah-fibres may evoke exaggerated responses in spinal
cord neurons that have underwent the process of
central sensitisation (see below). Recently, however,
the hypothesis was put forward that pain is not
generated by the injured nerve fibres themselves but
by intact nerve fibres in the vicinity of injured nerve
fibres. After an experimental lesion in the L5 dorsal
root spontaneous action potential discharges were
observed in C-fibres in the uninjured L4 dorsal root.
These fibres may be affected by the process of a
Wallerian degeneration [23].
Different mechanisms are thought to produce
ectopic discharges: changes in the expression of ionic
channels, pathological activation of axons by inflam-
matory mediators, and pathological activation of
injured nerve fibres by the sympathetic nervous
system. After nerve injury the expression of TTX-
sensitive sodium channels is increased, and the
expression of TTX-insensitive sodium channels is
decreased. These changes are thought to alter the
membrane properties of the neuron such that rapid
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342326
firing rates (bursting ectopic discharges) are favoured
[24].
Injured axons of primary afferent neurons may be
excited by inflammatory mediators, e.g. by bradyki-
nin, NO, and by cytokines (for references, see [25]).
The source of these inflammatory mediators may be
white bloods cells and Schwann cells around the
damaged nerve fibres. The sympathetic nervous
system does not activate primary afferents in normal
tissue but injured nerve fibres may become sensitive
to adrenergic mediators. This cross-talk may occur at
different sites. Adrenergic receptors may be expressed
at the sensory nerve fibre ending. A direct connection
between afferent and efferent fibres (so-called
bephapsesQ) is considered. Sympathetic endings are
expressed in increased numbers in the spinal ganglion
after nerve injury. The cell bodies of injured nerve
fibres are surrounded by bbasketsQ consisting of
sympathetic fibres [26].
2. Central pain pathways
Nociceptors activate synaptically nociceptive
dorsal horn neurons. The latter are either ascending
tract neurons or interneurons that are part of segmen-
tal motor or vegetative reflex pathways. Ascending
axons activate the thalamocortical system that produ-
ces the conscious pain sensation (see below). Thus,
the pain sensation is just one limited aspect of the
underlying nociceptive processes that include encod-
ing of noxious stimuli at the sensory nociceptive
endings and conscious and unconscious processing of
nociceptive input within the central nervous system.
During acute pain states the intensity of nociception
by and large determines the intensity of pain, i.e. the
nociceptive processes and the subjective experience
pain are closely related. This can be different in
chronic pain states.
Concerning nociception in joints noxious stimuli
are processed in several types of spinal cord neurons.
One class of neurons is only excited by stimulation of
deep tissue, and many of these neurons have a high
threshold. The latter neurons only respond to noxious
mechanical stimulation of the normal joint such as
hitting the joint or overrotating the joint. The receptive
field of these neurons is located at the joint (joint
capsules, ligaments) and in the adjacent muscles. The
receptive field can even include several joints such as
the knee and the ankle. Another class of neurons show
convergent inputs from skin and deep tissue. Typical-
ly these neurons are wide dynamic range neurons.
These cells respond weakly to innocuous stimuli and
strongly to noxious stimuli encoding stimulus inten-
sity at a particular site of the receptive field by the
discharge frequency [2].
Through ascending pathways spinal cord neurons
activate the lateral and medial thalamocortical
system. The lateral thalamocortical system consists
of relay nuclei in the lateral thalamus and the areas
SI and SII in the cortex. In this system the noxious
stimulus is analysed for its location, duration and
intensity, i.e. this system is important for the
discriminative aspect of the subjective experience
of pain. The medial thalamocortical system consists
of relay nuclei in the central and medial thalamus,
the anterior cingulate cortex (ACC), the insula, and
the prefrontal cortex. In these neuronal circuits the
affective component of pain is generated. Painful
stimuli elicit unpleasantness and aversive reactions
[27,28].
The spinal cord is influenced by descending tracts
that reduce or facilitate the nociceptive processing at
the spinal level. These pathways originate from
brainstem nuclei (in particular the periaquaeductal
grey, nucleus raphe magnus) and descend in the
dorsolateral funiculus of the spinal cord. These
descending pathways and segmental inhibitory neu-
rons provide significant control over the nociceptive
processing [28].
2.1. Central sensitization—increased sensitivity in the
central nervous system
Pathological nociceptive input often causes central
sensitization. Spinal sensitization is an increase of
excitability of spinal cord neurons [29]. Hyperexcit-
able spinal cord neurons are more susceptible to
peripheral inputs and respond, therefore, stronger to
stimulation. Central sensitization amplifies the pro-
cessing of nociceptive input and is thus an important
mechanism involved in clinically relevant pain states.
It consists of the following phenomena: (a) increase of
the responses to input from the injured or inflamed
region; (b) increase of responses to input from regions
adjacent to and even remote from the injured/inflamed
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 327
region although these areas are not injured/inflamed;
(c) expansion of the receptive fields of the spinal cord,
i.e. the total area from which the neuron is activated,
is enlarged. A consequence of spinal sensitization is
that in the spinal segments with input from the
lesioned/injured regions, a higher proportion of
neurons respond to stimulation of peripheral tissue.
Presumably, the latter accounts for secondary hyper-
algesia, i.e. hyperalgesia in normal tissue surrounding
the injured/inflamed area [2,30].
In many cases central sensitisation persists as long
as the nociceptive input persists, and it disappears
when the peripheral input is reduced. In other cases,
however, central sensitisation may outlast the periph-
eral nociceptive process. Possibly nociceptive inputs
have triggered a so-called long-term potentiation, a
persistent increase of synaptic efficacy [31].
Sensitization can also be observed at the thalamo-
cortical level. In polyarthritic rats, a large proportion
of neurons in the ventrobasal complex of the
thalamus respond to movements and gentle pressure
onto inflamed joints and often long-lasting after-
discharges were noted whereas only few neurons
respond to these stimuli in normal rats [32]. Similarly,
neurons in superficial cortical layers that do not
respond to joint stimulation in normal rats start to
respond to joint stimulation in polyarthritic rats [33].
These findings indicate substantial neuroplasticity at
the thalamocortical level that may contribute to
inflammatory pain.
Most nociceptive spinal cord neurons are tonical-
ly inhibited by descending inhibitory systems that
keep the spinal cord under control [34]. Neurons are
also inhibited by heterotopic noxious stimuli, in line
with the concept of diffuse noxious inhibitory
control (DNIC) thus implying that painful stimula-
tion at one site of the body may reduce the pain at
another site of the body. Tonic descending inhibition,
as well as heterotopic inhibitory influences, is
increased during acute inflammation. Interestingly,
however, tonic descending inhibition seems to be
normalized in the chronic stage of inflammation
raising the question which role descending inhibitory
systems play in the long-term range of chronic
disease [35]. Furthermore, descending spinal facili-
tation has also been observed [34], suggesting that
the central nervous system can modulate spinal pain
processing in either direction.
2.2. Molecular mechanisms of spinal sensitization
Central sensitization is induced and maintained by
the action of several receptor/transmitter systems. A
major role is played by glutamate, the main transmit-
ter in nociceptors. Glutamate excites postsynaptic
neurons by activating ionotropic receptors in the
subsynaptic membrane. Importantly, glutamate has
also the potential to induce hyperexcitability by
activating ionotropic N-methyl-d-aspartate (NMDA)
and metabotropic glutamate receptors in spinal cord
neurons. When NMDA receptors are opened by
glutamate, large amounts of calcium are flowing into
the neuron. Calcium ions induce second messenger
cascades that increase neuronal excitability [36].
Administration of antagonists to the NMDA receptor
can prevent central sensitisation, and established
hyperexcitability can be reduced by NMDA receptor
antagonists.
Neuropeptides and spinal prostaglandins are also
involved in the process of central sensitisation. Many
neurons in the spinal cord express receptors for the
tachykinins substance P, neurokinin A, and CGRP [1].
During acute inflammation in the joint the spinal
release of substance P, neurokinin A and CRGP from
nociceptors is increased [37–39], and these neuro-
peptides support the generation of spinal cord
hyperexcitability. Spinal application of antagonists to
these receptors attenuates the development of inflam-
mation-mediated hyperexcitability [40–42], probably
by a facilitation of glutamatergic synaptic transmis-
sion [43,44]. The role of prostaglandins is discussed
in detail in chapter 8.6.
2.3. Nociceptive versus neuropathic pain
Traditionally, inflammatory pain has been differ-
entiated from pain originating from direct injury to a
peripheral nerve (neuropathic pain). In the case of
inflammation the patients show spontaneous pain (in
the absence of stimulation) and/or hyperalgesia.
Hyperalgesia during joint inflammation is usually
characterized by the appearance of pain evoked by
normally innocuous stimuli such as movements of a
joint in the working range or palpation of an inflamed
joint, and by increased pain intensities when the joint
is being overrotated or overstretched. When nerve
damage is involved (e.g. during compression of a
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342328
nerve by a vertebral disc) the patient suffers from
bneuropathicQ pain. This pain is often characterized by
sudden severe belectricalQ pain that may be evoked by
movements or occur spontaneously, or it may appear
as burning pain. Neuropathic pain is often projected
into the innervation territory of the affected nerve.
Although the clinical features of inflammatory and
neuropathic pain differ substantially, recent data
suggest that local inflammation of the peripheral
nerves is a crucial part of the generation of neuro-
pathic pain [45,46]. Moreover, non-neuronal cells
have been shown to be active players in the process of
neuronal sensitization: glial cells activated by neuro-
nal damage can sensitize neurons by the release of the
chemokine fractalkine [47–49]. This interaction
exemplifies the tight link between inflammation and
nociception beyond the well known and studied
activity of inflammatory mediators on nociceptive
nerve endings in clinically inflamed tissue.
During acute pain states the intensity of nociceptor
discharge by and large determines the intensity of
pain, i.e. the nociceptive processes and the subjective
experience pain are closely related. This can be
different in chronic pain states. Originally pain was
called bchronicQ when it lasted longer than 6 months
[50]. In many chronic pain states the causal relation-
ship between nociception and pain is not tight and the
pain does not only reflect tissue damage. Chronic pain
may be accompanied by neuroendocrine dysregula-
tion, fatigue, dysphoria, and impaired physical and
even mental performance [51]. Multidisciplinary pain
research showed that in many cases rather psycho-
logical and social factors seem to determine the pain,
e.g. in many cases of low back pain [52]. In these
patients learning processes are major factors both for
the pathophysiology and for therapeutic approaches
[53–55].
3. Advances in pain therapy
Exciting progress is being made in discovering the
mechanisms that operate in sensory pathways to
generate the sensation of pain. Consequently, multiple
potentially useful targets for novel analgesics have
been identified. Clinical treatment of pain, however, is
still largely confined to opioids and non-steroidal anti-
inflammatory drugs. COX-2 selective NSAIDs (cox-
ibs) may be a clinical advance in terms of GI toxicity
but not in terms of other side effects or efficacy. Much
of currently available clinical treatment is only
partially effective and the increasing numbers of
elderly people in the population means a rising
prevalence of age-related painful conditions like
osteoarthritis that require successful pain treatment.
To bridge the gap between the advancing understand-
ing of the neurobiology of pain and the lack of
progress in clinical pain therapy a greater effort is
required to develop new analgesics and to change the
empirical pain treatment to a mechanism based and
individualized approach to pain management.
This chapter outlines some advances in the
pharmacology of pain with a focus on inflammatory
pain in arthritis.
3.1. Targeting prostaglandins: cyclooxygenases, pros-
taglandin synthases and receptors
Traditional NSAIDs and the selective COX-2
antagonists (Coxibs) are among the most commonly
used analgesics and anti-inflammatory drugs in the
treatment of arthritis. The major mechanism of action
is supposed to be the inhibition of cyclooxygenase
(COX-1) and/or COX-2 enzymes and thereby pros-
taglandin synthesis (reviewed in Steinmeyer and
Kontinnen). Prostaglandins and particularly PGE2
contribute to the sensitization of nociceptors and
mechanoreceptors in inflamed tissue including in-
flamed joints [56]. In addition to peripheral sensitizing
effects, centrally generated PGE2 plays an important
role in pain signaling. PGE2 is released in the dorsal
horns of the spinal cord following nociceptive
stimulation [57,58] and has multiple actions that
contribute to central sensitization, a central amplifi-
cation of sensory outflow from the spinal cord that is
responsible for the spread of sensitivity beyond the
site of injury [59]. These actions include (i) a
facilitation of neuropeptide release from central
nociceptor terminals [60,61], (ii) spinal disinhibition
by suppressing glycine receptor mediated inhibitory
currents [62,63] and (iii) increase of the excitability of
dorsal horn neurons by depolarizing postsynaptic
membranes [64–66]. Analgesia provided by COX-
inhibitors depends to a great extent on the inhibition
of central PGE2 production and is therefore not
directly linked to their anti-inflammatory effects.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 329
The facilitating PGE2 effects in the dorsal horn are
mediated through EP2 receptors expressed in super-
ficial layers of the spinal cord dorsal horn [67].
Intrathecal delivery of PGE2 in EP1 and EP3 receptor
knockout mice suggest that these receptor subtypes
are also involved in PGE2 induced allodynia or
hyperalgesias [68]. The EP1 receptor also mediates
acid-induced visceral pain hypersensitivity in humans
[69]. The specific role of diverse EP and other
prostaglandin receptor subtypes such as DP [70], IP
[71,72] and FP [73] is being investigated [74], but the
picture is still unclear, in part because of a lack of
specific inhibitors. COX-1 and COX-2 inhibitors
(traditional NSAIDs and COX-2 selective coxibs)
prevent the synthesis of the common intermediate
PGH2 and therefore general PG synthesis. Specific
PG synthases determine the type of PG that is formed
from PGH2, some of which have anti-inflammatory
actions such as PGD2 and its metabolite PGJ2 [75–
78]. Specific targeting of PG synthases [79–81] or EP-
receptors [74] might be an interesting novel strategy
to modulate PG-effects in the spinal cord and
periphery. The higher specificity may be associated
with reduced side effects.
3.1.1. NO-NSAIDs
NSAIDs with nitric oxide releasing properties,
referred to as NO-NSAIDs or CINODS (cycloox-
ygenase inhibiting NO donators), have been devel-
oped to combine the analgesic properties of PG
inhibition with gastroprotective properties of nitric
oxide. NO-NSAIDs are generated by adding a
nitroxybutyl or a nitrosothiol moiety to the parent
NSAID via a short-chain ester linkage. They release
small amounts of NO over prolonged periods of
time. Low concentrations of NO produce analgesia
probably due to nitrosylation and thereby modifica-
tion of mediators that are directly or indirectly
involved in pain signaling. At high concentrations
that are produced by the inducible nitric oxide
synthase (iNOS), nitric oxide rather contributes to
hyperalgesia and further tissue damage [82,83]. The
slow NO release provided by CINODS counteracts
NSAID-induced gastric damage by improving gastric
microcirculation and other gastrointestinal mucosal
defense mechanisms. Clinical trials show reduced
gastrointestinal toxicity of NO-NSAIDs when com-
pared with the parent drugs [84]. NO-NSAIDs have
stronger antinociceptive efficacy than conventional
NSAIDs in several animal models. NO-naproxen
was about 10-fold more effective than naproxen in
reducing acetic acid-induced writhing in mice [85] or
thermal and mechanical hyperalgesia in adjuvant
arthritis in rats [86]. NO-paracetamol and NO-aspirin
were also more effective than the parent drugs
[87,88]. Intravenous NO-paracetamol, but not para-
cetamol reduced the response of spinal cord neurons
to noxious mechanical and high-intensity electrical
stimulation [89,90]. The superiority of NO-NSAIDs
over standard NSAIDs is independent of COX-
inhibition. NO-NSAIDs are currently evaluated in
clinical trials [91].
3.1.2. LOX-COX inhibitors
LOX-COX inhibitors such as Licofelone (ML3000),
a competitive inhibitor of 5-lipoxygenase, COX-1 and
COX-2, is currently in clinical development for the
treatment of osteoarthritis. Licofelone decreases the
production of proinflammatory leukotrienes and
prostaglandins. The drug combines the analgesic
effects of NSAIDs and LOX-inhibitors with an
improved GI tolerability, the latter due to inhibition
of the synthesis of leukotrienes involved in GI
damage [92]. LOX-COX inhibitors reduce joint
destruction in a rat model of adjuvant arthritis [93]
and inhibit the progression of osteoarthritis in dogs
[94]. Inhibition of metalloproteinase MMP13 results
in a reduction of abnormal subchondral bone cell
metabolism in experimental dog osteoarthritis
[95,96]. Endoscopy data from a randomized, con-
trolled trial in healthy volunteers show that licofelone
is well tolerated [97]. Effects on gastric mucosa are
similar to placebo and superior to naproxen therapy
[97]. A 52-week long-term study found similar
efficacy of licofelone and naproxen in the treatment
of osteoarthritis. Licofelone also appears to be as
effective as the selective COX-2 inhibitor celecoxib
with a similar GI safety profile.
3.2. Anti-inflammatory and peripheral analgesic
efficacy of opioids and cannabinoids
3.2.1. Opioids (central effects reviewed in chapter of
Steinmeyer and Kontinnen)
Peripheral opioid receptors have been suggested
to be involved in analgesic and anti-inflammatory
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342330
effects of injected and endogenous opioids [98,99].
Local injection of opioids into peripheral inflamed
tissues causes potent local naloxone-reversible anti-
nociception in laboratory animals [100–105]. The
opioid-induced peripheral antinociception only
occurs in inflamed tissue where the number of
opioid receptors is increased [106–108] and is
abolished by constriction of the sciatic nerve
suggesting that opioid receptors are transported into
the periphery by axonal transport [106,109]. The
physiological importance of peripheral opioid recep-
tors was doubted until inflammation-attracted im-
mune cells were identified as the source of
endogenous opioid peptides. The release of these
endogenous ligands is triggered by sympathetic
neuron-derived nordrenaline release [110] and is a
form of communication between immune cells and
nociceptors, important for peripheral pain control
[99,111–115]. In clinical studies injection of opioids
into knee joints after knee surgery [116–120] or local
infiltration after dental surgery [121] caused pro-
longed postoperative analgesia in humans. A recent
study demonstrated analgesic effects of morphine
mouthwashes in patients with painful mucositis
[122,123]. An experimental pain study in healthy
subjects revealed peripheral analgesic effects of
morphine-6-glucuronide (M6G). At a low dose that
has no central effects, monitored by pupil size
measurements, M6G reduced pain in an inflamma-
tory skin and muscle pain model without effects on
electrically evoked pain [124]. Recently, 6-amino
acid conjugates of 14-O-methyloxymorphone that
have limited access to the central nervous system
were found to mediate antinociception at peripheral
sites [125]. Activation of peripheral opioid receptors
is associated with a reduction of direct inflammatory
signs such as plasma extravasation suggesting an
inhibition of the release of neurogenic inflammatory
mediators [126]. The inflammation-induced upregu-
lation of opioid receptors and the release of
endogenous opioids from immune cells may lead
to novel approaches for the development of periph-
erally acting opioid analgesics. Clinical investigation
now focuses on the development of new peripheral
opioid agonists as well as on ways to stimulate the
endogenous analgesic system in order to induce
effective peripheral analgesia with reduced central
side effects [127].
3.2.2. Cannabinoids
Cannabinoid and opioid systems share neuroana-
tomical, neurochemical, and pharmacological features
suggesting a crosstalk between both systems and
possibly in part complimentary or synergistic func-
tions [128]. The major active constituent of the plant
Cannabis sativa (marijuana), delta-9-tetrahydrocan-
nabinol (THC), and a variety of natural and synthetic
cannabinoids possess antinociceptive and anti-inflam-
matory activities demonstrated in various models of
somatic and visceral inflammatory pain [129,130] and
of neuropathic pain [131–133]. Anandamide, THC
and synthetic CB-receptor agonists reduce pain and
inflammation in collagen and Freund adjuvant arthri-
tis models [134–137] and prevent cartilage resorption,
in part, by inhibiting proteoglycan breakdown and
cytokine-induced, iNOS mediated nitric oxide over-
production in chondrocytes [138]. Most of the
biological actions of cannabinoids are mediated
through the cannabinoid receptors, CB-1 and CB-2,
but cannabinoids also activate vanilloid receptors.
Endogenous ligands for CB receptors (endocannabi-
noids) such as anandamide and 2-arachidonoyl-
glycerol (2-AG) are lipidic messengers derived from
arachidonic acid. They are released into the extracel-
lular space and rapidly inactivated by cellular re-
uptake and degradation by the membrane integrated
fatty acid amide hydrolase (FAAH). In the spinal cord
CB-1 receptors are primarily localized in superficial
laminae of the dorsal horn. No change of expression
after rhizotomy and colocalization with the protein
kinase C gamma subunit suggest that the majority of
CB-1 expression is on spinal interneurons [139]. The
peripheral analgesic effects of endocannabinoids
produced by local injection at the site of inflammation
can be attributed in part to neuronal mechanisms
acting through CB-1 and/or CB-2 receptors on
primary afferent neurons [140]. The anti-inflammato-
ry actions are probably mediated through CB-2
receptors expressed on immune cells and nociceptor
terminals [129,141]. Activation of the latter may
prevent release of neurogenic pro-inflammatory sub-
stances. CB-2 receptor activation in the periphery
stimulates a release of beta-endorphin from CB-2
positive keratinocytes, leading to peripheral mu-
opioid receptor activation [142]. Together these
effects explain the CB-2 receptor mediated inhibition
of C-fiber stimulation [143] and show that cannabi-
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 331
noids complement the neuro-immune crosstalk of
endogenous opioid peptides. The cannabinoid effects
contribute to local analgesic effects and endogenous
pain control. The major goal in the development of
cannabinoid-based analgesics is to separate the anti-
nociceptive effects from the psychotropic effects.
Therefore antinociceptive effects produced at the level
of primary nociceptors and immune cells are the most
attractive targets in this regard. The potential medical
applications of cannabis in the treatment of pain
syndromes, mainly painful muscle spasms and neu-
ropathic pain are currently investigated in clinical
trials [144].
3.3. Nuclear factor kappa B (NF-jB)
Since glucocorticoids were found to mediate at
least part of their anti-inflammatory effects through
inhibition of nuclear factor kappa B (NF-nB) [145]
this transcription factor has emerged as a most
interesting pharmaceutical target because a dysregu-
lation of NF-nB appears to be involved in various
pathological processes including chronic pain and
inflammation [146–150] and inflammation-evoked
bone destruction [151–153]. The role of NF-nB in
osteoclastogenesis was clearly demonstrated in double
NF-nB knockouts, lacking p50 and p52 NF-nBs. Thedouble, but not the single knockouts developed
osteopetrosis because of a defect in osteoclast
differentiation [154].
In unstimulated cells, NF-nB is normally inactive,
because it is retained in the cytoplasm by InBinhibitor proteins. Upon exposure to inflammatory
or other stress stimuli InB is phosphorylated [155],
ubiquitinated and degraded [156] allowing nuclear
translocation of NF-nB [157] and transcriptional
activation of NF-nB responsive genes. NF-nB enhan-
ces transcription of numerous pro-inflammatory and
pro-proliferative genes [158]. The phosphorylation of
InBs is catalyzed by an InB kinase complex (IKK)
[159] consisting of two catalytically active subunits
IKKa (IKK-1) and IKKh (IKK-2) [160,161] and a
varying number of regulatory IKKg subunits (NEMO)
[162]. IKK is activated by phosphorylation of IKKh[163]. Phosphorylation of IKKa has distinct effects on
gene transcription through stimulation of the alterna-
tive p100/p52 NF-nB pathway. IKK controls its own
activity by autophosphorylation that, at a certain level
results in its inhibition and increased sensitivity to
phosphatases [163]. A regulatory failure may cause
excessive production of pro-inflammatory or survival
factors. Interestingly, drugs used for a long time in the
treatment of chronic arthritis such as glucocorticoids,
gold salts [164,165], flurbiprofen and high doses of
salicylate inhibit NF-nB activation [145,150,166–
168]. Intra-articular gene transfer of a dominant
negative IKKh considerably reduced synovial inflam-
mation in rats [147]. Novel IKK inhibitors reverse
inflammatory hyperalgesia in various models of
inflammatory nociception [169]. In arthritis models,
IKK inhibitors reduced pain, osteoclastogenesis and
cartilage resorption [151,170]. Some herbal/fruit
constituents [171] and bee venom [172] that reduce
arthritis symptoms inhibit IKK activity what may be
the underlying mechanism of action. Leflunomide
used as a slow acting anti-rheumatic drug also inhibits
activation of NF-nB [173]. Inflamed synovial tissue
produces a variety of growth factors and cytokines
such as IL-1 and receptor activator of NF-nB ligand
(RANKL) [174,175]. Both IL-1 and RANKL act
through NF-nB activation and stimulate osteoclast
differentiation, activity and survival [174,175] and
thereby promote bone erosions [153]. RANKL is a
member of the TNF ligand superfamily of cytokines
that binds to its receptor, RANK and is essential for
osteoclast differentiation. In collagen induced arthritis
in mice blockade with osteoprotegerin (OPG), a decoy
receptor for RANKL, results in protection from bone
destruction [153]. Inhibition of NF-nB prevents or
reduces expression of multiple genes that regulate
inflammatory and osteoclastogenic responses, partic-
ularly metalloproteinases and cytokines. NF-nB is
therefore a centerpiece of inflammatory-osteolytic
arthritis and IKK inhibitors may attenuate progression
of joint destruction and reduce the pain. Specific and
potent inhibitors of IKKh and/or inducible IKKe are
being developed as novel analgesics and slow acting
anti-rheumatic drugs and are evaluated in phase I
clinical studies.
3.4. Anti-IL-1 and anti-TNFa
Anti-cytokine treatment directed against IL-1 or
TNFa is part of the multi-drug treatment strategy for
progressive rheumatoid arthritis. Anakinra is a recom-
binant human IL-1 receptor antagonist. In clinical
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342332
trials it reduces the signs and symptoms of active RA
and slows the rate of radiographic destruction.
Patients treated with anakinra also experienced a
reduction in new bone erosions and joint space
narrowing as compared with controls. Etanercept is
a soluble TNF-receptor fusion protein. It binds to
TNFa and beta, preventing each from interacting with
respective receptors. A double blind, randomised
study evaluating etanercept versus methotrexate found
a more rapid response with etanercept, but no
difference at twelve months [176]. In patients with
active RA, despite methotrexate, addition of etaner-
cept resulted in significant reduction of disease
activity and delay of radiographic progression or
improvement of radiological scores. Adalimumab is a
recombinant human IgG1 monoclonal antibody that
binds TNFa, thereby precluding binding to its
receptor. The monoclonal antibody also lyses cells
expressing the cytokine on their surface. Being a
human recombinant product, formation of anti-chi-
meric antibodies is reduced compared with infliximab,
a chimeric (mouse-human) monoclonal anti-TNFal-
pha antibody. Adalimumab increases efficacy of MTX
in clinical studies (similar to etanercept or infliximab)
[177,178]. The anti-cytokine drugs reduce pain in
patients with RA or ankylosing spondylitis by
reducing joint inflammation and bone destruction.
Both IL-1h and TNFa are also directly involved in
pain signalling in the spinal cord and contribute to the
development of inflammatory hyperalgesia and neu-
ropathic pain [179–182].
4. Potential novel targets for pain treatment in
arthritis
4.1. Acid sensing ion channels (ASICs)
Tissue acidosis is a dominant factor in inflamma-
tion and contributes to pain and hyperalgesia [183–
186]. Recent electrophysiological experiments have
strongly suggested the involvement of ASICs (ami-
loride-blockable proton-gated ion channels) expressed
in mammalian central and peripheral nervous systems
in nociception linked to acidosis [184,187–192].
Protons directly activate ASICs with subsequent
generation of action potentials [191,193,194]. Sensory
neurons from mice lacking the sensory neuron
specific ASIC-3 [188,190,195] do not respond to
acidic stimuli in vitro. ASIC expression in primary
afferent neurons increases in inflammatory conditions
[194], triggered by pro-inflammatory mediators in-
cluding nerve growth factor (NGF), serotonin, IL-1,
and bradykinin. A mixture of these mediators
increases the number of ASIC-expressing neurons
[196] and ASIC-like electrical current amplitudes on
sensory neurons [189,197,198] leading to hyperexcit-
ability. Locally applied NSAIDs reduce cutaneous and
corneal pain induced by acidic pH in the absence of
inflammation [199,200]. This effect is probably
mediated through a COX-independent direct inhibi-
tion of ASIC activity on sensory neurons. NSAIDs
also prevent the inflammation-induced increase of
ASIC expression [201]. These two effects are thus
proposed to play an important role in the analgesic
efficacy of NSAIDs in inflammatory pain, suggesting
that specific inhibitors might be useful as analgesics.
The first-identified potent and specific peptide blocker
of ASIC-1 channels is psalmotoxin 1 (PcTx1). It was
isolated from the venom of the South American
tarantula Psalmopoeus cambridgei [202]. Recently, a
new toxin (APETx2) from the sea anemone Antho-
pleura elegantissima has been identified. It inhibits
homo- and heteromeric ASIC-3 channels [203] and
may be a useful tool in further analysing the role of
ASIC-3 in pain signaling.
4.2. Tetrodotoxin resistant voltage gated sodium
channels (TTX resistant VGSCs)
Other ion channels that are specifically expressed
in damage-sensing sensory neurons include the
voltage sensitive TTX-resistant sodium channels
NaV1.7, NaV1.8 and NaV1.9. Using promoter ele-
ments of the NaV1.8 gene, transgenic mouse lines
were generated that express Cre recombinase selec-
tively in nociceptive and thermoreceptive neurons in
sensory ganglia indicating the discrete localization of
NaV1.8 [204,205]. Crossing NaV1.8 cre mice with
floxed NaV1.7 mice yielded nociceptor-specific
NaV1.7 deficiency [206]. These knockout mice
showed increased mechanical and thermal pain
thresholds and an abolished or strongly reduced
response to a range of stimuli, such as formalin,
carrageenan, complete Freund’s adjuvant, or nerve
growth factor [206]. NaV1.8 has also been implicated
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 333
in increased excitability of colonic sensory neurons in
experimental mouse colitis suggesting a role of these
channels in visceral pain [207]. The discrete localiza-
tion of these tetrodotoxin (TTX)-resistant sodium
channels in primary nociceptive sensory neurons
may provide a novel opportunity for the development
of drugs that specifically block these channels to
achieve efficacious pain relief with an acceptable
safety profile.
4.3. Transient receptor potential (TRP) channels
TRPV1 is a nociceptor-specific ion channel that
serves as the molecular target of capsaicin and is also
known as capsaicin receptor and vanilloid-1 receptor
(VR1). TRPV1 is activated by noxious heat (with a
thermal threshold N43 8C) or low extracellular pH,
both causing pain in vivo. Studies using TRPV1-
deficient mice have shown that this ion channel is
essential for thermal hyperalgesia [208]. The activity
of TRPV1 is modified by rapidly reversible phos-
phorylation and subcellular compartmentalization
leading to receptor sensitization or desensitization
[209–213]. Upregulation of TRPV1 transcription
during inflammation explains longer lasting heat
hypersensitivity [214,215]. Following experimental
nerve injury and in animal models of diabetic
neuropathy TRPV1 is present on neurons that do
not normally express TRPV1 [216,217]. Combined,
these findings imply an important role for increased
and/or aberrant TRPV1 expression in the development
of inflammatory hyperalgesia and neuropathic pain. In
humans, disease-related changes in TRPV1 expres-
sion have been described in e.g. inflammatory bowel
disease and irritable bowel syndrome [209]. The
mechanisms that regulate TRPV1 gene expression
under pathological conditions are unknown but a
better understanding of these pathways has obvious
implications for rational drug development.
In addition to TRPV1, there are five thermosensi-
tive ion channels in mammals. They all belong to the
TRP (transient receptor potential) super family. TRP
channels of the vanilloid family (TRPV1, TRPV2,
TRPV3, TRPV4) are excited by heat stimuli whereas
TRPM8 and TRPA1 (ANKTM1) are cold responsive
[218]. The TRP channels are expressed in primary
sensory neurons as well as other tissues where their
functions are less investigated. All TRP channels
exhibit distinct thermal activation thresholds that are
not fixed but may change under inflammatory
conditions contributing to the development of heat
or cold hypersensitivity. Menthol activates cold-
sensitive TRPM8 [218], whereas TRPA1 is activated
by pungent natural compounds present e.g. in
cinnamon oil, mustard oil, and ginger [219]. Brady-
kinin, an inflammatory peptide acting through its G
protein-coupled receptor, also activates TRPA1 [219].
TRPA1 activation elicits a painful sensation and may
explain why noxious cold can paradoxically be
perceived as burning pain. Particular emphasis is
given to the therapeutic utility of TRPV1 modulators.
Small molecule agonists, including capsaicin and
resiniferatoxin (RTX), are currently used for a number
of clinical syndromes, including neuropathic pain,
spinal detrusor hyperreflexia, and bladder hypersen-
sitivity. Antagonists of TRPV1 had limited in vivo
success so far, in part due to poor pharmacokinetic
properties.
4.4. Bradykinin receptors
Bradykinin (BK), a vasoactive, proinflammatory
nonapeptide, promotes cell adhesion molecule (CAM)
expression [220], leukocyte sequestration, inter-endo-
thelial gap formation, and protein extravasation [221]
in postcapillary venules. These effects are mediated
by bradykinin B1 and B2 receptors. Bradykinin B2
receptors are constitutively expressed in nerve termi-
nals, sensory ganglia and dorsal horn of the spinal
cord. Antagonists such as bradyzide reverse thermal
hyperalgesia and Freund’s complete adjuvant induced
mechanical hyperalgesia of the rat knee joint [222].
Bradykinin B1 receptors are upregulated in sensory
neurons following tissue or nerve injury [223], or
GDNF (glial derived neurotrophic factor)-treatment
[224]. B1 antagonists reduce hyperalgesia, the time
course of efficacy parallels the time course of B1
receptor upregulation [225]. A chronic constriction
injury of the rat sciatic nerve also induces bradykinin
B1 receptor expression in the corresponding DRGs
[223]. Bradykinin B1 receptor deficient mice are less
sensitive to chemical and thermal nociception and
show reduced activity-dependent facilitation (wind-
up) of nociceptive reflexes [226]. Development of
specific bradykinin B1 (and/or B2) antagonists will
further reveal potential clinical applications.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342334
The outline of currently available and potentially
novel analgesics shows that targeting opioid receptors
and prostaglandins still constitutes the basis of clinical
pain therapy. The potential of these pathways is not
fully exploited with available drugs. Peripherally
acting opioids or NSAIDs with nitric oxide releasing
properties are examples of some possible advances. In
addition, several new promising targets have been
identified including transcription factors, heat-, cold-
and acid-sensitive ion channels, cytokines, growth
factors and kinins. Extensive knowledge in the
specific contribution of these and additional factors
to the manifestation of pain with different aetiology
may allow for an individualized mechanism based
treatment of pain states in the future.
References
[1] M.J. Millan, The induction of pain: an integrative review,
Prog. Neurobiol. 57 (1999) 1–164.
[2] H.G. Schaible, B.D. Grubb, Afferent and spinal mechanisms
of joint pain, Pain 55 (1993) 5–54.
[3] B. Lynn, Neurogenic inflammation caused by cutaneous
polymodal receptors, Prog. Brain Res. 113 (1996) 361–368.
[4] P. Holzer, Neurogenic vasodilatation and plasma leakage in
the skin, Gen. Pharmacol. 30 (1998) 5–11.
[5] S. Mense, Nociception from skeletal muscle in relation to
clinical muscle pain, Pain 54 (1993) 241–289.
[6] C. Weidner, M. Schmelz, R. Schmidt, B. Hansson, H.O.
Handwerker, H.E. Torebjork, Functional attributes discrim-
inating mechano-insensitive and mechano-responsive C
nociceptors in human skin, J. Neurosci. 19 (1999)
10184–10190.
[7] M. Schmelz, R. Schmidt, H.O. Handwerker, H.E. Torebjork,
Encoding of burning pain from capsaicin-treated human skin
in two categories of unmyelinated nerve fibres, Brain 123
(2000) 560–571.
[8] M. Ringkamp, Y.B. Peng, G. Wu, T.V. Hartke, J.N. Camp-
bell, R.A. Meyer, Capsaicin responses in heat-sensitive and
heat-insensitive A-fiber nociceptors, J. Neurosci. 21 (2001)
4460–4468.
[9] M. Schmelz, K. Michael, C. Weidner, R. Schmidt, H.E.
Torebjork, H.O. Handwerker, Which nerve fibers mediate the
axon reflex flare in human skin?, NeuroReport 11 (2000)
645–648.
[10] M. Klede, H.O. Handwerker, M. Schmelz, Central origin of
secondary mechanical hyperalgesia, J. Neurophysiol. 90
(2003) 353–359.
[11] C. Weidner, M. Schmelz, R. Schmidt, B. Hansson, H.O.
Handwerker, H.E. Torebjork, Functional attributes discrimi-
nating mechano-insensitive and mechano-responsive C noci-
ceptors in human skin, J. Neurosci. 19 (1999) 10184–10190.
[12] K. Orstavik, C. Weidner, R. Schmidt, M. Schmelz, M.
Hilliges, E. Jørum, H. Handwerker, H.E. Torebjork, Patho-
logical C-fibres in patients with a chronic painful condition,
Brain 126 (2003) 567–578.
[13] K.J. Bar, U. Schurigt, A. Scholze, V.B. Segond, N. Stopfel,
R. Brauer, K.J. Halbhuber, H.G. Schaible, The expression
and localization of somatostatin receptors in dorsal root
ganglion neurons of normal and monoarthritic rats, Neuro-
science 127 (2004) 197–206.
[14] H.G. Schaible, A. Ebersberger, G.S. Von Banchet, Mecha-
nisms of pain in arthritis, Ann. N. Y. Acad. Sci. 966 (343-54)
(2002) 343–354.
[15] S.M. Carlton, J. Du, S. Zhou, R.E. Coggeshall, Tonic control
of peripheral cutaneous nociceptors by somatostatin recep-
tors, J. Neurosci. 21 (2001) 4042–4049.
[16] B. Heppelmann, M. Pawlak, Peripheral application of cyclo-
somatostatin, a somatostatin antagonist, increases the mecha-
nosensitivity of rat knee joint afferents, Neurosci. Lett. 259
(1999) 62–64.
[17] R.K. Banik, Y. Kozaki, J. Sato, L. Gera, K. Mizumura, B2
receptor-mediated enhanced bradykinin sensitivity of rat
cutaneous C-fiber nociceptors during persistent inflamma-
tion, J. Neurophysiol. 86 (2001) 2727–2735.
[18] S.M. Carlton, R.E. Coggeshall, Inflammation-induced up-
regulation of neurokinin 1 receptors in rat glabrous skin,
Neurosci. Lett. 326 (2002) 29–32.
[19] G.S. von Banchet, P.K. Petrow, R. Brauer, H.G. Schaible,
Monoarticular antigen-induced arthritis leads to pronounced
bilateral upregulation of the expression of neurokinin 1 and
bradykinin 2 receptors in dorsal root ganglion neurons of rats,
Arthritis Res. 2 (2000) 424–427.
[20] G.R. Lewin, A. Rueff, L.M. Mendell, Peripheral and central
mechanisms of NGF-induced hyperalgesia, Eur. J. Neurosci.
6 (1994) 1903–1912.
[21] V.B. Segond, A. Scholze, H.G. Schaible, Prostaglandin E2
increases the expression of the neurokinin1 receptor in adult
sensory neurones in culture: a novel role of prostaglandins,
Br. J. Pharmacol. 139 (2003) 672–680.
[22] C.N. Liu, M. Michaelis, R. Amir, M. Devor, Spinal nerve
injury enhances subthreshold membrane potential oscillations
in DRG neurons: relation to neuropathic pain, J. Neuro-
physiol. 84 (2000) 205–215.
[23] G. Wu, M. Ringkamp, T.V. Hartke, B.B. Murinson, J.N.
Campbell, J.W. Griffin, R.A. Meyer, Early onset of
spontaneous activity in uninjured C-fiber nociceptors after
injury to neighboring nerve fibers, J. Neurosci. 21 (2001)
(art-RC137).
[24] T.R. Cummins, S.D. Dib-Hajj, J.A. Black, S.G. Waxman,
Sodium channels and the molecular pathophysiology of pain,
Prog. Brain Res. 129 (3-19) (2000) 3–19.
[25] H.G. Schaible, F. Richter, Pathophysiology of pain, Langen-
beck’s Arch. Surg. 389 (2004) 237–243.
[26] W. Janig, J.D. Levine, M. Michaelis, Interactions of sympa-
thetic and primary afferent neurons following nerve injury and
tissue trauma, Prog. Brain Res. 113 (1996) 161–184.
[27] R.D. Treede, D.R. Kenshalo, R.H. Gracely, A. Jones, The
cortical representation of pain, Pain 79 (1999) 105–111.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 335
[28] A.I. Basbaum, T.M. Jessell, The perception of pain, in: E.R.
Kandell, T.M. Jessel (Eds.), Principles of Neural Science, Mc
Graw-Hill, New York, 1999, pp. 472–491.
[29] C.J. Woolf, Evidence for a central component of post-injury
pain hypersensitivity, Nature 306 (1983) 686–688.
[30] H.G. Schaible, A. Del Rosso, M. Matucci-Cerinic, Neuro-
genic aspects of inflammation, Rheum. Dis. Clin. North Am.
31 (2005) 77–101.
[31] J. Sandkuhler, X. Liu, Induction of long-term potentiation at
spinal synapses by noxious stimulation or nerve injury, Eur. J
Neurosci. 10 (1998) 2476–2480.
[32] M. Gautron, G. Guilbaud, Somatic responses of ventrobasal
thalamic neurones in polyarthritic rats, Brain Res. 237 (1982)
459–471.
[33] Y. Lamour, G. Guilbaud, J.C. Willer, Altered properties and
laminar distribution of neuronal responses to peripheral
stimulation in the SmI cortex of the arthritic rat, Brain Res.
273 (1983) 183–187.
[34] H. Vanegas, H.G. Schaible, Descending control of persistent
pain: inhibitory or facilitatory?, Brain Res. Rev. 46 (2004)
295–309.
[35] N. Danziger, J. Weil-Fugazza, D. Le Bars, D. Bouhassira,
Stage-dependent changes in the modulation of spinal
nociceptive neuronal activity during the course of inflamma-
tion, Eur. J. Neurosci. 13 (2001) 230–240.
[36] M.E. Fundytus, Glutamate receptors and nociception: impli-
cations for the drug treatment of pain, CNS Drugs 15 (2001)
29–58.
[37] H.G. Schaible, B. Jarrott, P.J. Hope, A.W. Duggan, Release
of immunoreactive substance P in the spinal cord during
development of acute arthritis in the knee joint of the cat: a
study with antibody microprobes, Brain Res. 529 (1990)
214–223.
[38] H.G. Schaible, U. Freudenberger, V. Neugebauer, R.U.
Stiller, Intraspinal release of immunoreactive calcitonin
gene-related peptide during development of inflammation
in the joint in vivo-a study with antibody microprobes in cat
and rat, Neuroscience 62 (1994) 1293–1305.
[39] P.J. Hope, B. Jarrott, H.G. Schaible, R.W. Clarke, A.W.
Duggan, Release and spread of immunoreactive neurokinin A
in the cat spinal cord in a model of acute arthritis, Brain Res.
533 (1990) 292–299.
[40] V. Neugebauer, F. Weiretter, H.G. Schaible, Involvement of
substance P and neurokinin-1 receptors in the hyperexcit-
ability of dorsal horn neurons during development of acute
arthritis in rat’s knee joint, J. Neurophysiol. 73 (1995)
1574–1583.
[41] V. Neugebauer, P. Rumenapp, H.G. Schaible, Calcitonin
gene-related peptide is involved in the spinal processing of
mechanosensory input from the rat’s knee joint and in the
generation and maintenance of hyperexcitability of dorsal
horn-neurons during development of acute inflammation,
Neuroscience 71 (1996) 1095–1109.
[42] V. Neugebauer, P. Rumenapp, H.G. Schaible, The role of
spinal neurokinin-2 receptors in the processing of nociceptive
information from the joint and in the generation and
maintenance of inflammation-evoked hyperexcitability of
dorsal horn neurons in the rat, Eur. J. Neurosci. 8 (1996)
249–260.
[43] A. Ebersberger, I.P. Charbel, H. Vanegas, H.G. Schaible,
Differential effects of calcitonin gene-related peptide and
calcitonin gene-related peptide 8-37 upon responses to N-
methyl-D-aspartate or (R, S)-alpha-amino-3-hydroxy-5-
methylisoxazole-4-propionate in spinal nociceptive neurons
with knee joint input in the rat, Neuroscience 99 (2000)
171–178.
[44] L. Urban, S.W. Thompson, A. Dray, Modulation of spinal
excitability: co-operation between neurokinin and excitatory
amino acid neurotransmitters, Trends Neurosci. 17 (1994)
432–438.
[45] C. Sommer, Painful neuropathies, Curr. Opin. Neurol. 16
(2003) 623–628.
[46] C. Sommer, M. Kress, Recent findings on how proinflam-
matory cytokines cause pain: peripheral mechanisms in
inflammatory and neuropathic hyperalgesia, Neurosci. Lett.
361 (2004) 184–187.
[47] L.R. Watkins, E.D. Milligan, S.F. Maier, Glial proinflam-
matory cytokines mediate exaggerated pain states: implica-
tions for clinical pain, Adv. Exp. Med. Biol. 521 (1–21)
(2003) 1–21.
[48] J. Wieseler-Frank, S.F. Maier, L.R. Watkins, Glial activation
and pathological pain, Neurochem. Int. 45 (2004) 389–395.
[49] I.N. Johnston, E.D. Milligan, J. Wieseler-Frank, M.G.
Frank, V. Zapata, J. Campisi, S. Langer, D. Martin, P.
Green, M. Fleshner, L. Leinwand, S.F. Maier, L.R. Watkins,
A role for proinflammatory cytokines and fractalkine in
analgesia, tolerance, and subsequent pain facilitation in-
duced by chronic intrathecal morphine, J. Neurosci. 24
(2004) 9353–9365.
[50] C.M. Russo, W.G. Brose, Chronic pain, Annu. Rev. Med. 49
(123–33) (1998) 123–133.
[51] C.R. Chapman, J. Gavrin, Suffering: the contributions of
persistent pain, Lancet 353 (1999) 2233–2237.
[52] N.A. Kendall, Psychosocial approaches to the prevention of
chronic pain: the low back paradigm, Baillieres Best, Pract.
Res. Clin. Rheumatol. 13 (1999) 545–554.
[53] H. Flor, Painful memories. Can we train chronic pain patients
to ’forget’ their pain?, EMBO Rep. 3 (2002) 288–291.
[54] H. Flor, B. Knost, N. Birbaumer, The role of operant
conditioning in chronic pain: an experimental investigation,
Pain 95 (2002) 111–118.
[55] K. Thieme, E. Gromnica-Ihle, H. Flor, Operant behavioral
treatment of fibromyalgia: a controlled study, Arthritis
Rheum. 49 (2003) 314–320.
[56] H.G. Schaible, R.F. Schmidt, Excitation and sensitization of
fine articular afferents from cat’s knee joint by prostaglandin
E2, J. Physiol. 403 (91–104) (1988) 91–104.
[57] A.B. Malmberg, T.L. Yaksh, Cyclooxygenase inhibition and
the spinal release of prostaglandin E2 and amino acids
evoked by paw formalin injection: a microdialysis study in
unanesthetized rats, J. Neurosci. 15 (1995) 2768–2776.
[58] G. Geisslinger, U. Muth-Selbach, O. Coste, G. Vetter, A.
Schrodter, H.G. Schaible, K. Brune, I. Tegeder, Inhibition of
noxious stimulus-induced spinal prostaglandin E2 release by
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342336
flurbiprofen enantiomers: a microdialysis study, J. Neuro-
chem. 74 (2000) 2094–2100.
[59] C.J. Woolf, A.E. King, Dynamic alterations in the cutaneous
mechanoreceptive fields of dorsal horn neurons in the rat
spinal cord, J. Neurosci. 10 (1990) 2717–2726.
[60] G.D. Nicol, D.K. Klingberg, M.R. Vasko, Prostaglandin E2
increases calcium conductance and stimulates release of
substance P in avian sensory neurons, J. Neurosci. 12 (1992)
1917–1927.
[61] C.M. Hingtgen, K.J. Waite, M.R. Vasko, Prostaglandins
facilitate peptide release from rat sensory neurons by
activating the adenosine 3V,5V-cyclic monophosphate trans-
duction cascade, J. Neurosci. 15 (1995) 5411–5419.
[62] R.J. Harvey, U.B. Depner, H. Wassle, S. Ahmadi, C. Heindl,
H. Reinold, T.G. Smart, K. Harvey, B. Schutz, O.M. Abo-
Salem, A. Zimmer, P. Poisbeau, H. Welzl, D.P. Wolfer, H.
Betz, H.U. Zeilhofer, U. Muller, GlyR alpha3: an essential
target for spinal PGE2-mediated inflammatory pain sensiti-
zation, Science 304 (2004) 884–887.
[63] S. Ahmadi, S. Lippross, W.L. Neuhuber, H.U. Zeilhofer,
PGE(2) selectively blocks inhibitory glycinergic neurotrans-
mission onto rat superficial dorsal horn neurons, Nat.
Neurosci. 5 (2002) 34–40.
[64] H. Baba, T. Kohno, K.A. Moore, C.J. Woolf, Direct
activation of rat spinal dorsal horn neurons by prostaglandin
E2, J. Neurosci. 21 (2001) 1750–1756.
[65] G.D. Nicol, M.R. Vasko, A.R. Evans, Prostaglandins
suppress an outward potassium current in embryonic rat
sensory neurons, J. Neurophysiol. 77 (1997) 167–176.
[66] A.R. Evans, M.R. Vasko, G.D. Nicol, The cAMP transduc-
tion cascade mediates the PGE2-induced inhibition of
potassium currents in rat sensory neurones, J. Physiol. 516
(1999) 163–178.
[67] F. Beiche, T. Klein, R. Nusing, W. Neuhuber, M. Goppelt-
Struebe, Localization of cyclooxygenase-2 and prostaglandin
E2 receptor EP3 in the rat lumbar spinal cord,
J. Neuroimmunol. 89 (1998) 26–34.
[68] T. Minami, H. Nakano, T. Kobayashi, Y. Sugimoto, F.
Ushikubi, A. Ichikawa, S. Narumiya, S. Ito, Characterization
of EP receptor subtypes responsible for prostaglandin E2-
induced pain responses by use of EP1 and EP3 receptor
knockout mice, Br. J. Pharmacol. 133 (2001) 438–444.
[69] S. Sarkar, A.R. Hobson, A. Hughes, J. Growcott, C.J. Woolf,
D.G. Thompson, Q. Aziz, The prostaglandin E2 receptor-1
(EP-1) mediates acid-induced visceral pain hypersensitivity
in humans, Gastroenterology 124 (2003) 18–25.
[70] N. Eguchi, T. Minami, N. Shirafuji, Y. Kanaoka, T. Tanaka,
A. Nagata, N. Yoshida, Y. Urade, S. Ito, O. Hayaishi, Lack of
tactile pain (allodynia) in lipocalin-type prostaglandin D
synthase-deficient mice, Proc. Natl. Acad. Sci. U. S. A. 96
(1999) 726–730.
[71] Y. Doi, T. Minami, M. Nishizawa, T. Mabuchi, H. Mori, S.
Ito, Central nociceptive role of prostacyclin (IP) receptor
induced by peripheral inflammation, NeuroReport 13 (2002)
93–96.
[72] T. Murata, F. Ushikubi, T. Matsuoka, M. Hirata, A.
Yamasaki, Y. Sugimoto, A. Ichikawa, Y. Aze, T. Tanaka,
N. Yoshida, A. Ueno, S. Oh-ishi, S. Narumiya, Altered pain
perception and inflammatory response in mice lacking
prostacyclin receptor, Nature 388 (1997) 678–682.
[73] T. Muratani, M. Nishizawa, S. Matsumura, T. Mabuchi, K.
Abe, K. Shimamoto, T. Minami, S. Ito, Functional
characterization of prostaglandin F2alpha receptor in the
spinal cord for tactile pain (allodynia), J. Neurochem. 86
(2003) 374–382.
[74] K.J. Bar, G. Natura, A. Telleria-Diaz, P. Teschner, R. Vogel,
E. Vasquez, H.G. Schaible, A. Ebersberger, Changes in the
effect of spinal prostaglandin E2 during inflammation:
prostaglandin E (EP1-EP4) receptors in spinal nociceptive
processing of input from the normal or inflamed knee joint,
J. Neurosci. 24 (2004) 642–651.
[75] L.B. Maggi Jr., H. Sadeghi, C. Weigand, A.L. Scarim, M.R.
Heitmeier, J.A. Corbett, Anti-inflammatory actions of 15-
deoxy-delta 12,14-prostaglandin J2 and troglitazone: evi-
dence for heat shock-dependent and-independent inhibition
of cytokine-induced inducible nitric oxide synthase expres-
sion, Diabetes 49 (2000) 346–355.
[76] Y. Tsubouchi, Y. Kawahito, M. Kohno, K. Inoue, T. Hla, H.
Sano, Feedback control of the arachidonate cascade in
rheumatoid synoviocytes by 15-deoxy-Delta(12,14)-prosta-
glandin J2, Biochem. Biophys. Res. Commun. 283 (2001)
750–755.
[77] S. Boyault, M.A. Simonin, A. Bianchi, E. Compe, B. Liagre,
D. Mainard, P. Becuwe, M. Dauca, P. Netter, B. Terlain, K.
Bordji, 15-Deoxy-delta12,14-PGJ2, but not troglitazone,
modulates IL-1beta effects in human chondrocytes by
inhibiting NF-kappaB and AP-1 activation pathways, FEBS
Lett. 501 (2001) 24–30.
[78] D.S. Straus, G. Pascual, M. Li, J.S. Welch, M. Ricote, C.H.
Hsiang, L.L. Sengchanthalangsy, G. Ghosh, C.K. Glass, 15-
deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in
the NF-kappa B signaling pathway, Proc. Natl. Acad. Sci. U.
S. A. 97 (2000) 4844–4849.
[79] C.E. Trebino, J.L. Stock, C.P. Gibbons, B.M. Naiman, T.S.
Wachtmann, J.P. Umland, K. Pandher, J.M. Lapointe, S.
Saha, M.L. Roach, D. Carter, N.A. Thomas, B.A. Durtschi,
J.D. McNeish, J.E. Hambor, P.J. Jakobsson, T.J. Carty, J.R.
Perez, L.P. Audoly, Impaired inflammatory and pain
responses in mice lacking an inducible prostaglandin E
synthase, Proc. Natl. Acad. Sci. U. S. A. 100 (2003)
9044–9049.
[80] T. Mabuchi, H. Kojima, T. Abe, K. Takagi, M. Sakurai, Y.
Ohmiya, S. Uematsu, S. Akira, K. Watanabe, S. Ito,
Membrane-associated prostaglandin E synthase-1 is required
for neuropathic pain, NeuroReport 15 (2004) 1395–1398.
[81] D. Kamei, K. Yamakawa, Y. Takegoshi, M. Mikami-
Nakanishi, Y. Nakatani, S. Oh-ishi, H. Yasui, Y. Azuma, N.
Hirasawa, K. Ohuchi, H. Kawaguchi, Y. Ishikawa, T. Ishii, S.
Uematsu, S. Akira, M. Murakami, I. Kudo, Reduced pain
hypersensitivity and inflammation in mice lacking micro-
somal prostaglandin e synthase-1, J. Biol. Chem. 279 (2004)
33684–33695.
[82] S.T. Meller, C.P. Cummings, R.J. Traub, G.F. Gebhart, The
role of nitric oxide in the development and maintenance of
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 337
the hyperalgesia produced by intraplantar injection of
carrageenan in the rat, Neuroscience 60 (1994) 367–374.
[83] S.T. Meller, G.F. Gebhart, Nitric oxide (NO) and nociceptive
processing in the spinal cord, Pain 52 (1993) 127–136.
[84] B.J. Whittle, Cyclooxygenase and nitric oxide systems in the
gut as therapeutic targets for safer anti-inflammatory drugs,
Curr. Opin. Pharmacol. 4 (2004) 538–545.
[85] N.M. Davies, A.G. Roseth, C.B. Appleyard, W. McKnight, P.
Del Soldato, A. Calignano, G. Cirino, J.L. Wallace, NO-
naproxen vs. naproxen: ulcerogenic, analgesic and anti-
inflammatory effects, Aliment. Pharmacol. Ther. 11 (1997)
69–79.
[86] C. Cicala, A. Ianaro, S. Fiorucci, A. Calignano, M. Bucci, R.
Gerli, L. Santucci, J.L. Wallace, G. Cirino, NO-naproxen
modulates inflammation, nociception and downregulates T
cell response in rat Freund’s adjuvant arthritis, Br. J.
Pharmacol. 130 (2000) 1399–1405.
[87] O.A. al Swayeh, L.E. Futter, R.H. Clifford, P.K. Moore,
Nitroparacetamol exhibits anti-inflammatory and anti-noci-
ceptive activity, Br. J. Pharmacol. 130 (2000) 1453–1456.
[88] O.A. al Swayeh, R.H. Clifford, P. Del Soldato, P.K. Moore, A
comparison of the anti-inflammatory and anti-nociceptive
activity of nitroaspirin and aspirin, Br. J. Pharmacol. 129
(2000) 343–350.
[89] E.A. Romero-Sandoval, J. Mazario, D. Howat, J.F. Herrero,
NCX-701 (nitroparacetamol) is an effective antinociceptive
agent in rat withdrawal reflexes and wind-up, Br. J.
Pharmacol. 135 (2002) 1556–1562.
[90] J.E. Keeble, P.K. Moore, Pharmacology and potential
therapeutic applications of nitric oxide-releasing non-steroi-
dal anti-inflammatory and related nitric oxide-donating
drugs, Br. J. Pharmacol. 137 (2002) 295–310.
[91] P. Zacharowski, K. Zacharowski, C. Donnellan, A. John-
ston, I. Vojnovic, P. Forte, P. Del Soldato, N. Benjamin, S.
O’Byrne, The effects and metabolic fate of nitroflurbiprofen
in healthy volunteers, Clin. Pharmacol. Ther. 76 (2004)
350–358.
[92] S. Fiorucci, E. Distrutti, O.M. de Lima, M. Romano, A.
Mencarelli, M. Barbanti, E. Palazzini, A. Morelli, J.L.
Wallace, Relative contribution of acetylated cyclo-oxygenase
(COX)-2 and 5-lip ooxygenase (LOX) in regulating gastric
mucosal integrity and adaptation to aspirin, FASEB J. 17
(2003) 1171–1173.
[93] R.E. Gay, M. Neidhart, F. Pataky, S. Tries, S. Laufer, S. Gay,
Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and
2 by ML3000 reduces joint destruction in adjuvant arthritis,
J. Rheumatol. 28 (2001) 2060–2065.
[94] D.V. Jovanovic, J.C. Fernandes, J. Martel-Pelletier, F.C.
Jolicoeur, P. Reboul, S. Laufer, S. Tries, J.P. Pelletier, In vivo
dual inhibition of cyclooxygenase and lipoxygenase by ML-
3000 reduces the progression of experimental osteoarthritis:
suppression of collagenase 1 and interleukin-1beta synthesis,
Arthritis Rheum. 44 (2001) 2320–2330.
[95] D. Lajeunesse, J. Martel-Pelletier, J.C. Fernandes, S. Laufer,
J.P. Pelletier, Treatment with licofelone prevents abnormal
subchondral bone cell metabolism in experimental dog
osteoarthritis, Ann. Rheum. Dis. 63 (2004) 78–83.
[96] J.P. Pelletier, C. Boileau, J. Brunet, M. Boily, D. Lajeunesse,
P. Reboul, S. Laufer, J. Martel-Pelletier, The inhibition of
subchondral bone resorption in the early phase of experi-
mental dog osteoarthritis by licofelone is associated with a
reduction in the synthesis of MMP-13 and cathepsin K, Bone
34 (2004) 527–538.
[97] P. Bias, A. Buchner, B. Klesser, S. Laufer, The gastrointes-
tinal tolerability of the LOX/COX inhibitor, licofelone, is
similar to placebo and superior to naproxen therapy in
healthy volunteers: results from a randomized, controlled
trial, Am. J. Gastroenterol. 99 (2004) 611–618.
[98] G. Kobal, Pain-related electrical potentials of the human
nasal mucosa elicited by chemical stimulation, Pain 22
(1985) 151–163.
[99] C. Stein, M. Schafer, A.H. Hassan, Peripheral opioid
receptors, Ann. Med. 27 (1995) 219–221.
[100] C. Stein, M.J. Millan, T.S. Shippenberg, A. Herz, Peripheral
effect of fentanyl upon nociception in inflamed tissue of the
rat, Neurosci. Lett. 84 (1988) 225–228.
[101] C. Stein, M.J. Millan, T.S. Shippenberg, K. Peter, A. Herz,
Peripheral opioid receptors mediating antinociception in
inflammation. Evidence for involvement of mu, delta and
kappa receptors, J. Pharmacol. Exp. Ther. 248 (1989)
1269–1275.
[102] C.G. Parsons, A. Czlonkowski, C. Stein, A. Herz, Peripheral
opioid receptors mediating antinociception in inflammation.
Activation by endogenous opioids and role of the pituitary-
adrenal axis, Pain 41 (1990) 81–93.
[103] J.D. Levine, Y.O. Taiwo, Involvement of the mu-opiate
receptor in peripheral analgesia, Neuroscience 32 (1989)
571–575.
[104] Y.A. Kolesnikov, S. Jain, R. Wilson, G.W. Pasternak,
Peripheral morphine analgesia: synergy with central sites
and a target of morphine tolerance, J. Pharmacol. Exp. Ther.
279 (1996) 502–506.
[105] S. Perrot, G. Guilbaud, V. Kayser, Effects of intraplantar
morphine on paw edema and pain-related behaviour in a
rat model of repeated acute inflammation, Pain 83 (1999)
249–257.
[106] A.H. Hassan, A. Ableitner, C. Stein, A. Herz, Inflammation
of the rat paw enhances axonal transport of opioid receptors
in the sciatic nerve and increases their density in the inflamed
tissue, Neuroscience 55 (1993) 185–195.
[107] M. Schafer, Y. Imai, G.R. Uhl, C. Stein, Inflammation
enhances peripheral mu-opioid receptor-mediated analgesia,
but not mu-opioid receptor transcription in dorsal root
ganglia, Eur. J. Pharmacol. 279 (1995) 165–169.
[108] C. Stein, M. Pfluger, A. Yassouridis, J. Hoelzl, K. Lehr-
berger, C. Welte, A.H. Hassan, No tolerance to peripheral
morphine analgesia in presence of opioid expression in
inflamed synovia, J. Clin. Invest. 98 (1996) 793–799.
[109] S.A. Mousa, Q. Zhang, N. Sitte, R. Ji, C. Stein, Beta-
Endorphin-containing memory-cells and mu-opioid receptors
undergo transport to peripheral inflamed tissue, J. Neuro-
immunol. 115 (2001) 71–78.
[110] W. Binder, S.A. Mousa, N. Sitte, M. Kaiser, C. Stein, M.
Schafer, Sympathetic activation triggers endogenous opioid
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342338
release and analgesia within peripheral inflamed tissue, Eur.
J. Neurosci. 20 (2004) 92–100.
[111] H. Machelska, P.J. Cabot, S.A. Mousa, Q. Zhang, C. Stein,
Pain control in inflammation governed by selectins, Nat.
Med. 4 (1998) 1425–1428.
[112] M. Schafer, S.A. Mousa, Q. Zhang, L. Carter, C. Stein,
Expression of corticotropin-releasing factor in inflamed tissue
is required for intrinsic peripheral opioid analgesia, Proc.
Natl. Acad. Sci. U. S. A. 93 (1996) 6096–6100.
[113] M. Schafer, S.A. Mousa, C. Stein, Corticotropin-releasing
factor in antinociception and inflammation, Eur. J. Pharma-
col. 323 (1997) 1–10.
[114] H.L. Rittner, A. Brack, H. Machelska, S.A. Mousa, M. Bauer,
M. Schafer, C. Stein, Opioid peptide-expressing leukocytes:
identification, recruitment, and simultaneously increasing
inhibition of inflammatory pain, Anesthesiology 95 (2001)
500–508.
[115] H. Machelska, S.A. Mousa, A. Brack, J.K. Schopohl, H.L.
Rittner, M. Schafer, C. Stein, Opioid control of inflammatory
pain regulated by intercellular adhesion molecule-1, J.
Neurosci. 22 (2002) 5588–5596.
[116] C. Stein, K. Comisel, E. Haimerl, A. Yassouridis, K.
Lehrberger, A. Herz, K. Peter, Analgesic effect of intraartic-
ular morphine after arthroscopic knee surgery, N. Engl. J.
Med. 325 (1991) 1123–1126.
[117] A. Whitford, M. Healy, G.P. Joshi, S.M. McCarroll, T.M.
O’Brien, The effect of tourniquet release time on the
analgesic efficacy of intraarticular morphine after arthroscop-
ic knee surgery, Anesth. Analg. 84 (1997) 791–793.
[118] G.P. Joshi, S.M. McCarroll, O.H. Brady, B.J. Hurson, G.
Walsh, Intra-articular morphine for pain relief after
anterior cruciate ligament repair, Br. J. Anaesth. 70
(1993) 87–88.
[119] G.P. Joshi, S.M. McCarroll, T.M. O’Brien, P. Lenane,
Intraarticular analgesia following knee arthroscopy, Anesth.
Analg. 76 (1993) 333–336.
[120] M.M. McSwiney, G.P. Joshi, P. Kenny, S.M. McCarroll,
Analgesia following arthroscopic knee surgery. A controlled
study of intra-articular morphine, bupivacaine or both
combined, Anaesth. Intensive Care 21 (1993) 201–203.
[121] R. Likar, R. Sittl, K. Gragger, W. Pipam, H. Blatnig, C.
Breschan, H.V. Schalk, C. Stein, M. Schafer, Peripheral
morphine analgesia in dental surgery, Pain 76 (1998)
145–150.
[122] L.C. Cerchietti, A.H. Navigante, M.R. Bonomi, M.A.
Zaderajko, P.R. Menendez, C.E. Pogany, B.M. Roth, Effect
of topical morphine for mucositis-associated pain following
concomitant chemoradiotherapy for head and neck carcino-
ma, Cancer 95 (2002) 2230–2236.
[123] L.C. Cerchietti, A.H. Navigante, M.W. Korte, A.M. Cohen,
P.N. Quiroga, E.C. Villaamil, M.R. Bonomi, B.M. Roth,
Potential utility of the peripheral analgesic properties of
morphine in stomatitis-related pain: a pilot study, Pain 105
(2003) 265–273.
[124] I. Tegeder, S. Meier, M. Burian, H. Schmidt, G. Geisslinger,
J. Lotsch, Peripheral opioid analgesia in experimental human
pain models, Brain 126 (2003) 1092–1102.
[125] S. Furst, P. Riba, T. Friedmann, J. Timar, M. Al Khrasani, I.
Obara, W. Makuch, M. Spetea, J. Schutz, R. Przewlocki, B.
Przewlocka, H. Schmidhammer, Peripheral versus central
antinociceptive actions of 6-amino acid-substituted deriva-
tives of 14-O-methyloxymorphone in acute and inflamma-
tory pain in the rat, J. Pharmacol. Exp. Ther. 312 (2005)
609–618.
[126] A. Romero, E. Planas, R. Poveda, S. Sanchez, O. Pol, M.M.
Puig, Anti-exudative effects of opioid receptor agonists in a
rat model of carrageenan-induced acute inflammation of the
paw, Eur. J. Pharmacol. 511 (2005) 207–217.
[127] W. Janson, C. Stein, Peripheral opioid analgesia, Curr.
Pharm. Biotechnol. 4 (2003) 270–274.
[128] S.M. Tham, J.A. Angus, E.M. Tudor, C.E. Wright, Syner-
gistic and additive interactions of the cannabinoid agonist
CP55,940 with mu opioid receptor and alpha2-adrenoceptor
agonists in acute pain models in mice, Br. J. Pharmacol. 144
(2005) 875–884.
[129] S.I. Jaggar, F.S. Hasnie, S. Sellaturay, A.S. Rice, The anti-
hyperalgesic actions of the cannabinoid anandamide and the
putative CB2 receptor agonist palmitoylethanolamide in
visceral and somatic inflammatory pain, Pain 76 (1998)
189–199.
[130] H. Guhring, J. Schuster, M. Hamza, M. Ates, C.E. Kotalla, K.
Brune, HU-210 shows higher efficacy and potency than
morphine after intrathecal administration in the mouse
formalin test, Eur. J. Pharmacol. 429 (2001) 127–134.
[131] G. Lim, B. Sung, R.R. Ji, J. Mao, Upregulation of spinal
cannabinoid-1-receptors following nerve injury enhances the
effects of Win 55,212-2 on neuropathic pain behaviors in
rats, Pain 105 (2003) 275–283.
[132] D.A. Scott, C.E. Wright, J.A. Angus, Evidence that CB-1 and
CB-2 cannabinoid receptors mediate antinociception in
neuropathic pain in the rat, Pain 109 (2004) 124–131.
[133] B. Costa, M. Colleoni, S. Conti, A.E. Trovato, M. Bianchi,
M.L. Sotgiu, G. Giagnoni, Repeated treatment with the
synthetic cannabinoid WIN 55,212-2 reduces both hyper-
algesia and production of pronociceptive mediators in a rat
model of neuropathic pain, Br. J. Pharmacol. 141 (2004)
4–8.
[134] M.L. Cox, S.P. Welch, The antinociceptive effect of Delta9-
tetrahydrocannabinol in the arthritic rat, Eur. J. Pharmacol.
493 (2004) 65–74.
[135] P.F. Sumariwalla, R. Gallily, S. Tchilibon, E. Fride, R.
Mechoulam, M. Feldmann, A novel synthetic, nonpsychoac-
tive cannabinoid acid (HU-320) with antiinflammatory
properties in murine collagen-induced arthritis, Arthritis
Rheum. 50 (2004) 985–998.
[136] S.D. Gauldie, D.S. McQueen, R. Pertwee, I.P. Chessell,
Anandamide activates peripheral nociceptors in normal and
arthritic rat knee joints, Br. J. Pharmacol. 132 (2001)
617–621.
[137] A.M. Malfait, R. Gallily, P.F. Sumariwalla, A.S. Malik, E.
Andreakos, R. Mechoulam, M. Feldmann, The nonpsychoac-
tive cannabis constituent cannabidiol is an oral anti-arthritic
therapeutic in murine collagen-induced arthritis, Proc. Natl.
Acad. Sci. U. S. A. 97 (2000) 9561–9566.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 339
[138] E.C. Mbvundula, R.A. Bunning, K.D. Rainsford, Effects of
cannabinoids on nitric oxide production by chondrocytes and
proteoglycan degradation in cartilage, Biochem. Pharmacol.
69 (2005) 635–640.
[139] W.P. Farquhar-Smith, M. Egertova, E.J. Bradbury, S.B.
McMahon, A.S. Rice, M.R. Elphick, Cannabinoid CB(1)
receptor expression in rat spinal cord, Mol. Cell. Neurosci. 15
(2000) 510–521.
[140] J.D. Richardson, S. Kilo, K.M. Hargreaves, Cannabinoids
reduce hyperalgesia and inflammation via interaction with
peripheral CB1 receptors, Pain 75 (1998) 111–119.
[141] S.J. Elmes, M.D. Jhaveri, D. Smart, D.A. Kendall, V.
Chapman, Cannabinoid CB2 receptor activation inhibits
mechanically evoked responses of wide dynamic range
dorsal horn neurons in naive rats and in rat models of
inflammatory and neuropathic pain, Eur. J. Neurosci. 20
(2004) 2311–2320.
[142] M.M. Ibrahim, F. Porreca, J. Lai, P.J. Albrecht, F.L. Rice, A.
Khodorova, G. Davar, A. Makriyannis, T.W. Vanderah, H.P.
Mata, T.P. Malan Jr., CB2 cannabinoid receptor activation
produces antinociception by stimulating peripheral release of
endogenous opioids, Proc. Natl. Acad. Sci. U. S. A. 102
(2005) 3093–3098.
[143] A.G. Nackley, A.M. Zvonok, A. Makriyannis, A.G. Hoh-
mann, Activation of cannabinoid CB2 receptors suppresses
C-fiber responses and windup in spinal wide dynamic range
neurons in the absence and presence of inflammation,
J. Neurophysiol. 92 (2004) 3562–3574.
[144] K.B. Svendsen, T.S. Jensen, F.W. Bach, Does the cannabi-
noid dronabinol reduce central pain in multiple sclerosis?
Randomised double blind placebo controlled crossover trial,
BMJ 329 (2004) 253.
[145] N. Auphan, J.A. DiDonato, C. Rosette, A. Helmberg, M.
Karin, Immunosuppression by glucocorticoids: inhibition of
NF-kappa B activity through induction of I kappa B
synthesis, Science 270 (1995) 286–290.
[146] R. Marok, P.G. Winyard, A. Coumbe, M.L. Kus, K. Gaffney,
S. Blades, P.I. Mapp, C.J. Morris, D.R. Blake, C. Kaltsch-
midt, P.A. Baeuerle, Activation of the transcription factor
nuclear factor-kappaB in human inflamed synovial tissue,
Arthritis Rheum. 39 (1996) 583–591.
[147] P.P. Tak, D.M. Gerlag, K.R. Aupperle, D.A. van de Geest, M.
Overbeek, B.L. Bennett, D.L. Boyle, A.M. Manning, G.S.
Firestein, Inhibitor of nuclear factor kappaB kinase beta is a
key regulator of synovial inflammation, Arthritis Rheum. 44
(2001) 1897–1907.
[148] I. Tegeder, E. Niederberger, E. Israr, H. Guhring, K. Brune,
C. Euchenhofer, S. Grosch, G. Geisslinger, Inhibition of NF-
kappaB and AP-1 activation by R-and S-flurbiprofen,
FASEB J. 15 (2001) 595–597.
[149] M.F. Neurath, S. Pettersson, K.H. Meyer zum Buschenfelde,
W. Strober, Local administration of antisense phosphoro-
thioate oligonucleotides to the p65 subunit of NF-kappa B
abrogates established experimental colitis in mice, Nat. Med.
2 (1996) 998–1004.
[150] E. Kopp, S. Ghosh, Inhibition of NF-kappa B by sodium
salicylate and aspirin, Science 265 (1994) 956–959.
[151] S. Dai, T. Hirayama, S. Abbas, Y. Abu-Amer, The IkappaB
kinase (IKK) inhibitor, NEMO-binding domain peptide,
blocks osteoclastogenesis and bone erosion in inflammatory
arthritis, J. Biol. Chem. 279 (2004) 37219–37222.
[152] J.C. Clohisy, B.C. Roy, C. Biondo, E. Frazier, D. Willis, S.L.
Teitelbaum, Y. Abu-Amer, Direct inhibition of NF-kappa B
blocks bone erosion associated with inflammatory arthritis,
J. Immunol. 171 (2003) 5547–5553.
[153] E. Jimi, K. Aoki, H. Saito, F. D’Acquisto, M.J. May, I.
Nakamura, T. Sudo, T. Kojima, F. Okamoto, H. Fukushima,
K. Okabe, K. Ohya, S. Ghosh, Selective inhibition of NF-
kappa B blocks osteoclastogenesis and prevents inflamma-
tory bone destruction in vivo, Nat. Med. 10 (2004) 617–624.
[154] V. Iotsova, J. Caamano, J. Loy, Y. Yang, A. Lewin, R. Bravo,
Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2,
Nat. Med. 3 (1997) 1285–1289.
[155] J. DiDonato, F. Mercurio, C. Rosette, J. Wu-Li, H. Suyang,
S. Ghosh, M. Karin, Mapping of the inducible IkappaB
phosphorylation sites that signal its ubiquitination and
degradation, Mol. Cell. Biol. 16 (1996) 1295–1304.
[156] Y. Gao, S. Lecker, M.J. Post, A.J. Hietaranta, J. Li, R. Volk,
M. Li, K. Sato, A.K. Saluja, M.L. Steer, A.L. Goldberg, M.
Simons, Inhibition of ubiquitin-proteasome pathway-mediat-
ed I kappa B alpha degradation by a naturally occurring
antibacterial peptide, J. Clin. Invest. 106 (2000) 439–448.
[157] Y.Z. Lin, S.Y. Yao, R.A. Veach, T.R. Torgerson, J. Hawiger,
Inhibition of nuclear translocation of transcription factor NF-
kappa B by a synthetic peptide containing a cell membrane-
permeable motif and nuclear localization sequence, J. Biol.
Chem. 270 (1995) 14255–14258.
[158] H.L. Pahl, Activators and target genes of Rel/NF-kappaB
transcription factors, Oncogene 18 (1999) 6853–6866.
[159] E. Zandi, Y. Chen, M. Karin, Direct phosphorylation of
IkappaB by IKKalpha and IKKbeta: discrimination between
free and NF-kappaB-bound substrate, Science 281 (1998)
1360–1363.
[160] F. Mercurio, H. Zhu, B.W. Murray, A. Shevchenko, B.L.
Bennett, J. Li, D.B. Young, M. Barbosa, M. Mann, A.
Manning, A. Rao, IKK-1 and IKK-2: cytokine-activated
IkappaB kinases essential for NF-kappaB activation, Science
278 (1997) 860–866.
[161] J.A. DiDonato, M. Hayakawa, D.M. Rothwarf, E. Zandi, M.
Karin, A cytokine-responsive IkappaB kinase that activates
the transcription factor NF-kappaB, Nature 388 (1997)
548–554.
[162] D.M. Rothwarf, E. Zandi, G. Natoli, M. Karin, IKK-gamma
is an essential regulatory subunit of the IkappaB kinase
complex, Nature 395 (1998) 297–300.
[163] M. Delhase, M. Hayakawa, Y. Chen, M. Karin, Positive and
negative regulation of IkappaB kinase activity through
IKKbeta subunit phosphorylation, Science 284 (1999)
309–313.
[164] K.I. Jeon, J.Y. Jeong, D.M. Jue, Thiol-reactive metal
compounds inhibit NF-kappa B activation by blocking I
kappa B kinase, J. Immunol. 164 (2000) 5981–5989.
[165] J.P. Yang, J.P. Merin, T. Nakano, T. Kato, Y. Kitade, T.
Okamoto, Inhibition of the DNA-binding activity of NF-
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342340
kappa B by gold compounds in vitro, FEBS Lett. 361 (1995)
89–96.
[166] A. Ray, K.E. Prefontaine, Physical association and functional
antagonism between the p65 subunit of transcription factor
NF-kappa B and the glucocorticoid receptor, Proc. Natl.
Acad. Sci. U. S. A. 91 (1994) 752–756.
[167] R.I. Scheinman, P.C. Cogswell, A.K. Lofquist, A.S. Baldwin
Jr., Role of transcriptional activation of I kappa B alpha in
mediation of immunosuppression by glucocorticoids, Science
270 (1995) 283–286.
[168] M.J. Yin, Y. Yamamoto, R.B. Gaynor, The anti-inflammatory
agents aspirin and salicylate inhibit the activity of I(kappa)B
kinase-beta, Nature 396 (1998) 77–80.
[169] I. Tegeder, E. Niederberger, R. Schmidt, S. Kunz, H.
Guhring, O. Ritzeler, M. Michaelis, G. Geisslinger, Specific
Inhibition of IkappaB kinase reduces hyperalgesia in
inflammatory and neuropathic pain models in rats,
J. Neurosci. 24 (2004) 1637–1645.
[170] P.L. Podolin, J.F. Callahan, B.J. Bolognese, Y.H. Li, K.
Carlson, T.G. Davis, G.W. Mellor, C. Evans, A.K. Roshak,
Attenuation of murine collagen-induced arthritis by a novel,
potent, selective small molecule inhibitor of IkappaB Kinase
2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-
thiophenecarboxamide), occurs via reduction of proinflam-
matory cytokines and antigen-induced T cell Proliferation,
J. Pharmacol. Exp. Ther. 312 (2005) 373–381.
[171] Y. Takada, Y. Kobayashi, B.B. Aggarwal, Evodiamine
abolishes constitutive and inducible NF-{kappa}B activation
by inhibiting I{kappa}B{alpha} kinase activation, thereby
suppressing NF-{kappa}B-regulated antiapoptotic and meta-
static gene expression, Up-regulating apoptosis, and inhibit-
ing invasion, J. Biol. Chem. 280 (2005) 17203–17212.
[172] H.J. Park, S.H. Lee, D.J. Son, K.W. Oh, K.H. Kim, H.S.
Song, G.J. Kim, G.T. Oh, d.Y. Yoon, J.T. Hong, Anti-
arthritic effect of bee venom: inhibition of inflammation
mediator generation by suppression of NF-kappaB through
interaction with the p50 subunit, Arthritis Rheum. 50 (2004)
3504–3515.
[173] M. Urushibara, H. Takayanagi, T. Koga, S. Kim, M. Isobe, Y.
Morishita, T. Nakagawa, M. Loeffler, T. Kodama, H.
Kurosawa, T. Taniguchi, The antirheumatic drug leflunomide
inhibits osteoclastogenesis by interfering with receptor
activator of NF-kappa B ligand-stimulated induction of
nuclear factor of activated T cells c1, Arthritis Rheum. 50
(2004) 794–804.
[174] J.M. Quinn, N.J. Horwood, J. Elliott, M.T. Gillespie, T.J.
Martin, Fibroblastic stromal cells express receptor activator
of NF-kappa B ligand and support osteoclast differentiation,
J. Bone Miner. Res. 15 (2000) 1459–1466.
[175] N. Udagawa, N. Takahashi, E. Jimi, K. Matsuzaki, T.
Tsurukai, K. Itoh, N. Nakagawa, H. Yasuda, M. Goto, E.
Tsuda, K. Higashio, M.T. Gillespie, T.J. Martin, T. Suda,
Osteoblasts/stromal cells stimulate osteoclast activation
through expression of osteoclast differentiation factor/
RANKL but not macrophage colony-stimulating factor:
receptor activator of NF-kappa B ligand, Bone 25 (1999)
517–523.
[176] L. Klareskog, H.D. van der, J.P. de Jager, A. Gough, J.
Kalden, M. Malaise, M.E. Martin, K. Pavelka, J. Sany, L.
Settas, J. Wajdula, R. Pedersen, S. Fatenejad, M. Sanda,
Therapeutic effect of the combination of etanercept and
methotrexate compared with each treatment alone in patients
with rheumatoid arthritis: double-blind randomised con-
trolled trial, Lancet 363 (2004) 675–681.
[177] L.B. van de Putte, R. Rau, F.C. Breedveld, J.R. Kalden, M.G.
Malaise, P.L. van Riel, M. Schattenkirchner, P. Emery, G.R.
Burmester, H. Zeidler, H.M. Moutsopoulos, K. Beck, H.
Kupper, Efficacy and safety of the fully human anti-tumour
necrosis factor alpha monoclonal antibody adalimumab
(D2E7) in DMARD refractory patients with rheumatoid
arthritis: a 12 week, phase II study, Ann. Rheum. Dis. 62
(2003) 1168–1177.
[178] M.C. Hochberg, J.K. Tracy, M. Hawkins-Holt, R.H. Flores,
Comparison of the efficacy of the tumour necrosis factor
alpha blocking agents adalimumab, etanercept, and inflix-
imab when added to methotrexate in patients with active
rheumatoid arthritis, Ann. Rheum. Dis. 62 (Suppl 2:ii13-6)
(2003) ii13– ii16.
[179] T.A. Samad, K.A. Moore, A. Sapirstein, S. Billet, A.
Allchorne, S. Poole, J.V. Bonventre, C.J. Woolf, Interleu-
kin-1beta-mediated induction of Cox-2 in the CNS contrib-
utes to inflammatory pain hypersensitivity, Nature 410
(2001) 471–475.
[180] A. Ledeboer, E.M. Sloane, E.D. Milligan, M.G. Frank, J.H.
Mahony, S.F. Maier, L.R. Watkins, Minocycline attenuates
mechanical allodynia and proinflammatory cytokine ex-
pression in rat models of pain facilitation, Pain 115 (2005)
71–83.
[181] U. Hoheisel, T. Unger, S. Mense, Excitatory and modulatory
effects of inflammatory cytokines and neurotrophins on
mechanosensitive group IV muscle afferents in the rat, Pain
114 (2005) 168–176.
[182] M. Schafers, C.I. Svensson, C. Sommer, L.S. Sorkin, Tumor
necrosis factor-alpha induces mechanical allodynia after
spinal nerve ligation by activation of p38 MAPK in primary
sensory neurons, J. Neurosci. 23 (2003) 2517–2521.
[183] K.H. Steen, A.E. Steen, P.W. Reeh, A dominant role of
acid pH in inflammatory excitation and sensitization of
nociceptors in rat skin, in vitro, J. Neurosci. 15 (1995)
3982–3989.
[184] R. Waldmann, G. Champigny, F. Bassilana, C. Heurteaux, M.
Lazdunski, A proton-gated cation channel involved in acid-
sensing, Nature 386 (1997) 173–177.
[185] H.U. Zeilhofer, D. Swandulla, P.W. Reeh, M. Kress, Ca2+
permeability of the sustained proton-induced cation current in
adult rat dorsal root ganglion neurons, J. Neurophysiol. 76
(1996) 2834–2840.
[186] M. Kress, H.U. Zeilhofer, Capsaicin, protons and heat: new
excitement about nociceptors, Trends Pharmacol. Sci. 20
(1999) 112–118.
[187] T. Sugiura, K. Dang, K. Lamb, K. Bielefeldt, G.F. Gebhart,
Acid-sensing properties in rat gastric sensory neurons from
normal and ulcerated stomach, J. Neurosci. 25 (2005)
2617–2627.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342 341
[188] K.A. Sluka, M.P. Price, N.M. Breese, C.L. Stucky, J.A.
Wemmie, M.J. Welsh, Chronic hyperalgesia induced by
repeated acid injections in muscle is abolished by the loss of
ASIC3, but not ASIC1, Pain 106 (2003) 229–239.
[189] J.A. Wemmie, J. Chen, C.C. Askwith, A.M. Hruska-Hage-
man, M.P. Price, B.C. Nolan, P.G. Yoder, E. Lamani, T.
Hoshi, J.H. Freeman Jr., M.J. Welsh, The acid-activated ion
channel ASIC contributes to synaptic plasticity, learning, and
memory, Neuron 34 (2002) 463–477.
[190] C.C. Chen, A. Zimmer, W.H. Sun, J. Hall, M.J. Brownstein,
A. Zimmer, A role for ASIC3 in the modulation of high-
intensity pain stimuli, Proc. Natl. Acad. Sci.U. S. A. 99
(2002) 8992–8997.
[191] S.P. Sutherland, C.J. Benson, J.P. Adelman, E.W. McCleskey,
Acid-sensing ion channel 3 matches the acid-gated current in
cardiac ischemia-sensing neurons, Proc. Natl. Acad. Sci. U.
S. A. 98 (2001) 711–716.
[192] D.C. Immke, E.W. McCleskey, Lactate enhances the acid-
sensing Na+channel on ischemia-sensing neurons, Nat.
Neurosci. 4 (2001) 869–870.
[193] A. Baron, R. Waldmann, M. Lazdunski, ASIC-like, proton-
activated currents in rat hippocampal neurons, J. Physiol. 539
(2002) 485–494.
[194] L.J. Wu, B. Duan, Y.D. Mei, J. Gao, J.G. Chen, M. Zhuo, L.
Xu, M. Wu, T.L. Xu, Characterization of acid-sensing ion
channels in dorsal horn neurons of rat spinal cord, J. Biol.
Chem. 279 (2004) 43716–43724.
[195] C.C. Chen, S. England, A.N. Akopian, J.N. Wood, A sensory
neuron-specific, proton-gated ion channel, Proc. Natl. Acad.
Sci. U. S. A. 95 (1998) 10240–10245.
[196] J. Mamet, A. Baron, M. Lazdunski, N. Voilley, Proinflam-
matory mediators, stimulators of sensory neuron excitability
via the expression of acid-sensing ion channels, J. Neurosci.
22 (2002) 10662–10670.
[197] E. Deval, A. Baron, E. Lingueglia, H. Mazarguil, J.M. Zajac,
M. Lazdunski, Effects of neuropeptide SF and related
peptides on acid sensing ion channel 3 and sensory neuron
excitability, Neuropharmacology 44 (2003) 662–671.
[198] O. Yermolaieva, A.S. Leonard, M.K. Schnizler, F.M.
Abboud, M.J. Welsh, Extracellular acidosis increases neuro-
nal cell calcium by activating acid-sensing ion channel 1a,
Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 6752–6757.
[199] N.G. Jones, R. Slater, H. Cadiou, P. McNaughton, S.B.
McMahon, Acid-induced pain and its modulation in humans,
J. Neurosci. 24 (2004) 10974–10979.
[200] K.H. Steen, P.W. Reeh, H.W. Kreysel, Dose-dependent
competitive block by topical acetylsalicylic and salicylic
acid of low pH-induced cutaneous pain, Pain 64 (1996)
71–82.
[201] N. Voilley, J. de Weille, J. Mamet, M. Lazdunski, Nonsteroid
anti-inflammatory drugs inhibit both the activity and the
inflammation-induced expression of acid-sensing ion chan-
nels in nociceptors, J. Neurosci. 21 (2001) 8026–8033.
[202] P. Escoubas, C. Bernard, G. Lambeau, M. Lazdunski, H.
Darbon, Recombinant production and solution structure of
PcTx1, the specific peptide inhibitor of ASIC1a proton-gated
cation channels, Protein Sci. 12 (2003) 1332–1343.
[203] S. Diochot, A. Baron, L.D. Rash, E. Deval, P. Escoubas, S.
Scarzello, M. Salinas, M. Lazdunski, A new sea anemone
peptide, APETx2, inhibits ASIC3, a major acid-sensitive
channel in sensory neurons, EMBO J. 23 (2004) 1516–1525.
[204] N. Agarwal, S. Offermanns, R. Kuner, Conditional gene
deletion in primary nociceptive neurons of trigeminal ganglia
and dorsal root ganglia, Genesis 38 (2004) 122–129.
[205] L.C. Stirling, G. Forlani, M.D. Baker, J.N. Wood, E.A.
Matthews, A.H. Dickenson, M.A. Nassar, Nociceptor-specif-
ic gene deletion using heterozygous NaV1.8-Cre recombi-
nase mice, Pain 113 (2005) 27–36.
[206] M.A. Nassar, L.C. Stirling, G. Forlani, M.D. Baker, E.A.
Matthews, A.H. Dickenson, J.N. Wood, Nociceptor-specific
gene deletion reveals a major role for Nav1.7 (PN1) in acute
and inflammatory pain, Proc. Natl. Acad. Sci. U. S. A. 101
(2004) 12706–12711.
[207] M.J. Beyak, N. Ramji, K.M. Krol, M.D. Kawaja, S.J. Vanner,
Two TTX-resistant Na+ currents in mouse colonic dorsal root
ganglia neurons and their role in colitis-induced hyperexcit-
ability, Am. J. Physiol.: Gasterointest. Liver Physiol. 287
(2004) G845–G855.
[208] M.J. Caterina, A. Leffler, A.B. Malmberg, W.J. Martin, J.
Trafton, K.R. Petersen-Zeitz, M. Koltzenburg, A.I. Basbaum,
D. Julius, Impaired nociception and pain sensation in mice
lacking the capsaicin receptor, Science 288 (2000) 306–313.
[209] P. Geppetti, M. Trevisani, Activation and sensitisation of the
vanilloid receptor: role in gastrointestinal inflammation and
function, Br. J. Pharmacol. 141 (2004) 1313–1320.
[210] N.R. Gavva, L. Klionsky, Y. Qu, L. Shi, R. Tamir, S.
Edenson, T.J. Zhang, V.N. Viswanadhan, A. Toth, L.V.
Pearce, T.W. Vanderah, F. Porreca, P.M. Blumberg, J. Lile, Y.
Sun, K. Wild, J.C. Louis, J.J. Treanor, Molecular determi-
nants of vanilloid sensitivity in TRPV1, J. Biol. Chem. 279
(2004) 20283–20295.
[211] G. Bhave, H.J. Hu, K.S. Glauner, W. Zhu, H. Wang, D.J.
Brasier, G.S. Oxford, R.W. Gereau, Protein kinase C
phosphorylation sensitizes but does not activate the capsaicin
receptor transient receptor potential vanilloid 1 (TRPV1),
Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 12480–12485.
[212] V. Vlachova, J. Teisinger, K. Susankova, A. Lyfenko, R.
Ettrich, L. Vyklicky, Functional role of C-terminal cytoplas-
mic tail of rat vanilloid receptor 1, J. Neurosci. 23 (2003)
1340–1350.
[213] D.P. Mohapatra, C. Nau, Desensitization of capsaicin-
activated currents in the vanilloid receptor TRPV1 is
decreased by the cyclic AMP-dependent protein kinase
pathway, J. Biol. Chem. 278 (2003) 50080–50090.
[214] T.D. Wilson-Gerwing, M.V. Dmyterko, D.W. Zochodne,
J.M. Johnston, V.M. Verge, Neurotrophin-3 suppresses
thermal hyperalgesia associated with neuropathic pain and
attenuates transient receptor potential vanilloid receptor-1
expression in adult sensory neurons, J. Neurosci. 25 (2005)
758–767.
[215] R.R. Ji, T.A. Samad, S.X. Jin, R. Schmoll, C.J. Woolf, p38
MAPK activation by NGF in primary sensory neurons after
inflammation increases TRPV1 levels and maintains heat
hyperalgesia, Neuron 36 (2002) 57–68.
H.-G. Schaible et al. / Advanced Drug Delivery Reviews 58 (2006) 323–342342
[216] M.H. Rashid, M. Inoue, S. Bakoshi, H. Ueda, Increased
expression of vanilloid receptor 1 on myelinated primary
afferent neurons contributes to the antihyperalgesic effect
of capsaicin cream in diabetic neuropathic pain in mice,
J. Pharmacol. Exp. Ther. 306 (2003) 709–717.
[217] S. Hong, J.W. Wiley, Early painful diabetic neuropathy is
associated with differential changes in the expression and
function of vanilloid receptor 1, J. Biol. Chem. 280 (2005)
618–627.
[218] A.M. Peier, A. Moqrich, A.C. Hergarden, A.J. Reeve, D.A.
Andersson, G.M. Story, T.J. Earley, I. Dragoni, P. McIntyre,
S. Bevan, A. Patapoutian, A TRP channel that senses cold
stimuli and menthol, Cell 108 (2002) 705–715.
[219] M. Bandell, G.M. Story, S.W. Hwang, V. Viswanath, S.R.
Eid, M.J. Petrus, T.J. Earley, A. Patapoutian, Noxious cold
ion channel TRPA1 is activated by pungent compounds and
bradyknin, Neuron 41 (2004) 849–857.
[220] I.M. Sainz, A.B. Uknis, I. Isordia-Salas, R.A. Dela Cadena,
R.A. Pixley, R.W. Colman, Interactions between bradykinin
(BK) and cell adhesion molecule (CAM) expression in
peptidoglycan-polysaccharide (PG-PS)-induced arthritis,
FASEB J. 18 (2004) 887–889.
[221] S.C. Cruwys, N.E. Garrett, M.N. Perkins, D.R. Blake, B.L.
Kidd, The role of bradykinin B1 receptors in the maintenance
of intra-articular plasma extravasation in chronic antigen-
induced arthritis, Br. J. Pharmacol. 113 (1994) 940–944.
[222] G.M. Burgess, M.N. Perkins, H.P. Rang, E.A. Campbell,
M.C. Brown, P. McIntyre, L. Urban, E.K. Dziadulewicz, T.J.
Ritchie, A. Hallett, C.R. Snell, R. Wrigglesworth, W. Lee, C.
Davis, S.B. Phagoo, A.J. Davis, E. Phillips, G.S. Drake, G.A.
Hughes, A. Dunstan, G.C. Bloomfield, Bradyzide, a potent
non-peptide B(2) bradykinin receptor antagonist with long-
lasting oral activity in animal models of inflammatory
hyperalgesia, Br. J. Pharmacol. 129 (2000) 77–86.
[223] M.H. Rashid, M. Inoue, M. Matsumoto, H. Ueda, Switching
of bradykinin-mediated nociception following partial sciatic
nerve injury in mice, J. Pharmacol. Exp. Ther. 308 (2004)
1158–1164.
[224] V. Vellani, O. Zachrisson, P.A. McNaughton, Functional
bradykinin B1 receptors are expressed in nociceptive neuro-
nes and are upregulated by the neurotrophin GDNF,
J. Physiol. 560 (2004) 391–401.
[225] C.R. Tonussi, S.H. Ferreira, Bradykinin-induced knee joint
incapacitation involves bradykinin B2 receptor mediated
hyperalgesia and bradykinin B1 receptor-mediated nocicep-
tion, Eur. J. Pharmacol. 326 (1997) 61–65.
[226] J.B. Pesquero, R.C. Araujo, P.A. Heppenstall, C.L. Stucky,
J.A. Silva Jr., T. Walther, S.M. Oliveira, J.L. Pesquero, A.C.
Paiva, J.B. Calixto, G.R. Lewin, M. Bader, Hypoalgesia
and altered inflammatory responses in mice lacking kinin
B1 receptors, Proc. Natl. Acad. Sci. U. S. A. 97 (2000)
8140–8145.