Mechanisms underlying joint pain
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Transcript of Mechanisms underlying joint pain
MECHANISMS
DRUG DISCOVERY
TODAY
DISEASE
Drug Discovery Today: Disease Mechanisms Vol. 3, No. 3 2006
Editors-in-Chief
Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA
Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
Pain
Mechanisms underlying joint painIstvan Nagy1, Katalin V. Lukacs2, Laszlo Urban3,*1Department of Anaesthesiology and Intensive Care, Imperial College London, London, UK2School of Medicine, Chelsea and Westminster Hospital, London, UK3Preclinical Compound Profiling, Lead Discovery Center, Discovery Technologies, Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue,
Cambridge, MA 02139, USA
Joint pain is associated with injury, inflammation of the
joint and severe remodeling of the subchondrial bone.
The leading reason of articular pain is osteo- and rheu-
matoid arthritis. The most important component of
joint pain is sensitization of high threshold nociceptors,
which release neuropeptides, express excitatory recep-
tors and ion channels. Ongoing hyperexcitability of
nociceptors results in permanent CNS changes con-
tributing to the maintenance of chronic pain.
*Corresponding author: L. Urban ([email protected])
1740-6765/$ � 2006 Published by Elsevier Ltd. DOI: 10.1016/j.ddmec.2006.10.002
Section Editors:Frank Porreca – University of Arizona, Tucson, USAMichael Ossipov – University of Arizona, Tucson, USA
ents, because they are activated only after sensitization by
Introduction
One of the most frequent chronic pain sensations people
experience is associated with pathological conditions of the
joints. Although injuries, infections and systemic diseases
could produce short-term arthralgias, the most common
reasons for joint pain are osteoarthritis (OA) and rheumatoid
arthritis (RA). About 10% of the world’s population over 60
suffer from OA, and about 1% are affected by RA. In contrast
to acute pain caused by injury, pain associated with OA and
RA does not promote restoration of function. Instead, it
worsens the long-term functional outcome and quality of
life. Current therapies for OA or RA are often inadequate and
carry considerable adverse reactions. The development of
new analgesics is hampered by the lack of understanding
the complex pathways involved in the development and
maintenance of these diseases.
Although, joint pain has both peripheral and central
(spinal and brain) components [1,2], the present review
concentrates on the peripheral mechanisms, because they
are pivotal in the initiation and maintenance of pain in OA
and RA.
Sensory innervation of joints
Fibers innervating joints generally respond to mechanical
stimuli, but some are called ‘silent’ polymodal primary affer-
inflammatory agents. Specific nociceptors, which innervate
the joint, belong to the class of thinly myelinated (Ad) or to
unmyelinated I fibers. They can be activated by noxious
mechanical stimuli, such as overstretching the joint, but
some of them form the class of polymodal sensory primary
afferents, which in addition to mechanical stimuli responds
to noxious thermal- and chemical stimuli. They express
various types of receptors and ion channels, which are essen-
tial for neurotransduction. A subpopulation produces neu-
ropeptides and other neurogenic substances, which are
released both in the spinal cord and to the joint tissue.
The central release couples nociceptors with spinal neurones,
whereas the peripheral release induces neurogenic inflamma-
tion, such as plasma protein extravasation, vasodilation and
accumulation of immune cells in the joint. The special group
of silent fibers is not activated even by noxious stimuli under
physiological conditions; however, they can be sensitized
and start responding to non-noxious stimuli during inflam-
mation [3,4].
The innervationof the joint ishighly specific: (1)myelinated
Aa-, Ab-, thin myelinated Ad- and the unmyelinated C-sensory
357
Drug Discovery Today: Disease Mechanisms | Pain Vol. 3, No. 3 2006
fibers contribute to the sensory innervation of the capsule,
ligaments, periosteum, subchondral bone and menisci; (2)
only C-fibers innervate the synovial membrane and (3) the
articular cartilage has no nerve supply [5,6]. It is estimated that
about 80% of the total number of sensory fibers supplying the
joints belongs to the unmyelinated C primary afferents [3,7,8].
About 15–35% of the small caliber fibers are peptidergic, con-
taining substance P (SP) and calcitonin-gene related peptide
(CGRP) [9,10,11].
In general, while Aa, Ab and a proportion of Ad fibers can
be activated by innocuous light pressure and stretch, these
fibers do not contribute to the generation of joint pain; their
main function is ‘proprioception’. Large proportion of the Ad-
fibers and virtually all C-fibers are solely responsive to nox-
ious stimuli. The responsiveness of these fibers to mechan-
ical, chemical and thermal stimuli can be enhanced by the
induction of receptor and ion channel expression. Nerve
Growth Factor (NGF) is one of the major factors that can
produce such effects [12]. The increased responsiveness,
called sensitization is evident both by reduced activation
threshold to the level of innocuous stimuli and increased
impulse generation of the fibers [4]. NGF, however, is only
one factor that produces sensitization. Many inflammatory
mediators, such as prostaglandins and bradykinin have simi-
lar effects. They can also stimulate increased neuropeptide
production in the peptidergic fibers. The decreased threshold
and the enhanced neuropeptide production cause hypersen-
sitivity of the nociceptive system during inflammation.
The sensitization phenomenon is the most striking in
silent fibers [13,14]. Silent fibers account at least for the third
of the C-fiber population [3]. Although our knowledge about
silent fibers innervating the joint is relatively limited, it is
well established that cutaneous fibers with similar modalities
play a strong role in neurogenic inflammation in humans
[14,15].
Molecular characteristics of C-fibers innervating joints
C-fibers, including the peptidergic fibers express a series of
membrane molecules that can be activated by various che-
mical and physical stimuli. The modality of pain experienced
in joints affected by OA and RA is predominantly mechanical,
it develops within the normal moving range of the joint and
is generally described as throbbing or stabbing. The molecular
characteristics of the joint fibers associated with the above
sensations is not completely understood, however, recent
studies suggest that a broad variety of receptor and channel
proteins expressed on joint nociceptors can be the transdu-
cers. For direct activation by inflammatory mediators, bra-
dykinin, B1 and B2 receptors, prostaglandin EP1 and EP2 and
histamine receptors are expressed in joint nociceptors [16].
Primary afferents have large populations of neurotransmitter
receptors, such as muscarinic, P2X, adrenergic, opioid [17],
cannabinoid (CB1) and 5-HT, which provide plenty of oppor-
358 www.drugdiscoverytoday.com
tunities for direct modulation of excitability. Most peptider-
gic nociceptors express receptors for neurokinins, such as
substance P (NK-1 receptors), neuropeptide Y (NPY, Y1,
Y2); [18], somatostatin (SOM-1,2,3,4) and calcitonin gene-
related peptide (CGRP) [18a]. In general, opioids, somatos-
tatin and cannabinoids act as inhibitors of nociceptor
activation, however their up- or downregulation during
inflammation defines their hyperalgesic potency. It has been
shown recently, that all four SOM receptor subtypes are
present in joint fibers and SOM-2 is downregulated in mono-
arthritis leading to reduction of inhibition of primary afferent
activation [19].
Specific ion channels, such as members of the acid sensing
ion channels (ASICs) and transient receptor potential (TRP)
superfamily provide sites for pH and heat sensitization and
activation. ASICs are expressed in C fibers, activated by acidic
pH; however, recent studies revealed that they are also direct
targets of some NSAIDs [20]. The TRPV1 receptor is activated
by capsaicin, protons and noxious heat, whereas other mem-
bers of the super family (TRPV2,3,4,8 and TRPA1) are likely to
be involved only in thermal nociception [21]. TRPV8 is
expressed in large and small caliber fibers, however TRPV1
expression is largely restricted to C fibers [22]. Interestingly,
those fibers that express these two TRPs have also tyrosine
kinase (trk) receptors, which are activated by NGF [23]. Both
trk and cytokine receptor activation can modulate the phe-
notype of the fibers and contribute to the sensitization of
silent fibers [12,24].
Other, voltage gated ion channels, such as K+, Na+ and Ca2+
channels also contribute to the activation of primary affer-
ents. TTX-insensitive Na channels play a particularly promi-
nent role in nociceptor function (see later).
Mechanisms involved in the development of joint pain
Joint pain in arthritis is characterized by spontaneous pain in
addition to hyperalgesia and allodynia (pain sensation
induced by non-noxious stimuli, such as touch), which are
considered the consequences of both peripheral and central
sensitization [1,3]. RA-affected joints and the surrounding
tissues show increased sensitivity to noxious stimuli [25].
Activation of these sensitized fibers, through triggering a
series of changes in the responsiveness of neurons in the
central nervous system, results in pain sensation. Desensiti-
zation or degeneration of the sensitized fibers by capsaicin
results in reduced pain [26,27]. This is one of many observa-
tions which supports our present knowledge, that pain asso-
ciated with arthritis is largely due to sensitization of the
primary afferents, in particular of nociceptors innervating
the joint. As a consequence, the activation threshold of the
polymodal nociceptors will be reduced and fibers will be
activated by non-noxious stimuli, such as gentle move within
the normal range of the joint or light touch (mechanical
allodynia). Also, inflammatory mediators, pH changes and
Vol. 3, No. 3 2006 Drug Discovery Today: Disease Mechanisms | Pain
Figure 1. Peripheral and central components contribute to the development and maintenance of chronic joint pain. Both non-neuronal and neuronal
elements play an important role in peripheral sensitization of nociceptors. Central components reflect on increased transmitter release, upregulation of
receptor population and rearrangement of synaptic connections.
moderate heat stimuli will activate these fibers under the
inflammatory conditions. In addition to the sensitization of
the regular high threshold polymodal nociceptors, the silent
fibers will be sensitized by inflammatory mediators as well. A
special feature of the sensitized silent fibers is the long lasting
firing to the application of capsaicin [28]. The ‘awakening’ of
the silent fiber population has an important contribution to
the initiation of spinal sensitization [13,29], which is a major
component of chronic pain states.
Ongoing activity in these and other high threshold poly-
modal nociceptors will create a high level of spinal dorsal
horn activity by the excessive release of transmitters, includ-
ing glutamate and neuropeptides, such CGRP and substance
P [30,31]. One of the major elements of central sensitization is
NMDA receptor activation, which is, at least partially,
enhanced by the release of the above mentioned neuropep-
tides [32]. In addition to the high level of neurotransmitter
release, there is evidence for upregulation of various neuro-
transmitter receptors and enzymes in the dorsal root ganglia
(DRG) owing to the increased activity and by direct effects of
inflammatory mediators [16]. For summary of peripheral and
central components of chronic joint pain (Fig. 1).
Peripheral activation and sensitization of joint
afferents
At present, the most broadly used anti-inflammatory and
antihyperalgesic agents for attenuation of joint pain are
NSAIDs and selective COX-2 enzyme inhibitors. Inhibition
of the COX-1,2 enzymes blocks prostaglandin synthesis,
particularly the production of PGE-2 which is a powerful
inflammatory mediator and can sensitize nociceptors inner-
vating joints [16]. COX-1 is constitutively expressed, whereas
COX-2 is an inducible form of the enzyme that becomes a
prominent player in inflammatory conditions [33]. Inhibi-
tion of either of the two COX enzymes or the separate
blockade of COX-2 produces significant antihyperalgesic
activity [34,35].
Although the pain-inducing mechanism of PGE2 is not
fully understood, there is clear evidence that it can directly
enhance the excitability of the TTX-resistant Na channel,
expressed on the unmyelinated fibers [36]. It is anticipated
that the expression of COX enzymes is not only upregulated
during arthritis in the inflamed joint but also in the spinal
cord. Blockade of the spinal enzyme seems to be important
for the antihyperalgesic effects of NSAIDs and selective COX-
2 inhibitors [16]. However, NSAIDs and COX-2 inhibitors
have largely symptomatic effects and do not cure arthritis or
any other joint disease associated with pain. PGE2 is only one
of the many inflammatory mediators contributing to the
pathogenesis of arthritis and joint pain. Individual blockade
of prostaglandin receptors, therefore, may not result in a
strong antihyperalgesic activity. On the contrary, as men-
tioned in the previous chapter, recent studies found that
some NSAIDs block ASIC channels directly, which could
explain their enhanced antihyperalgesic and analgesic activ-
ity [20]. This finding seems to make lots of sense as the
different degree of analgesic effect of various NSAIDs were
difficult to explain. ASIC channel activation is very likely
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Table 1. Targets and related therapies for joint pain
Target Strategic approach
to target
Expected outcome of intervention at target
(e.g. reduction in neurofibrillary tangle formation)
Who is working on the target Therapies in trial (if applicable) Refs
TNFaa Soluble TNF-receptor
fusion protein
Reduction in disease activity RA, including pain.
Clinical trials show positive effect when
used with methotrexate.
Broad interest: Bayer, Wyeth, Amgen,
Abbott Labs, Celltech
Clinical trials: adalimumab;
etanercept; infliximab
[41,47]
IL-1b Recombinant human IL-1
antagonist
Reduction in disease activity RA, including pain Academia and several pharmaceutical
and biotech companies
Clinical trials: anakinra [43,48]
COX-1,2c Nonselective inhibitors:
NSAIDsd
Effects at both peripheral and central sites;
significant antiinflammatory effect;
antihyperalgesic effects vary between
different compounds.
More than 20 NSAIDs are registered
for clinical use
NSAIDs are broadly used in
arthritic pain syndromes
[49]
COX-2 Selective COX-2
inhibitors
Effects at both peripheral and central sites;
significant antiinflammatory and
antihyperalgesic effects due to inhibition of
prostaglandin synthesis;
less GI activity than seen with NSAIDs
Broad interest by many
pharmaceutical companies (Pfizer,
Merck, Novartis)
Coxibs are in the clinics: Celebrex,
Prexige, (Vioxx withdrawn)
[49,50]
Opiates Peripheral m and k
opioid receptors
Opioid recepots are expressed on primary afferents
and immune cells in the periphery;
peripheralized selective agonists could
produce antinociception without CNS effects
Broad interest in pharmaceutical
industry and clinical applications
Promising clinical studies with
topical use of morphine
[17,51]
PGE2e Receptor inhibition EP1f receptor inhibitors might be useful
antiinflammatory and analgesic
No specific inhibitors publishedfor
clinical use
No clinical data No clinical reference
[52]
ASICg Channel blocker Expected analgesic activity; COX inhibitors
have a direct effect on ASIC channels
Relatively new target, projects are
at early phase of drug discovery
Psalmotoxin, APETx2: not in
clinical trials
No clinical reference
TRPV1h Channel blocker or
modulator
Expected strong inhibitory effect on nociceptors;
Block of transduction and impulse
propagation in C fibers could produce
highly selective analgesic effects
Many pharmaceutical companies
are working on this target
(e.g., GSK, Merck)
No small molecule available
for clinical trials; natural
products capsaicin and
resiniferatoxin are used topically
[53]
TTX-resistant
Na channeliChannel blocker Inhibitors are expected to have a selective blocking
effect on nociceptors with good analgesic activity
Broad interest in academia and
pharmaceutical industry;
difficult target
No small molecule available
for clinical trials
No clinical reference
[55]
CCR-1j Receptor inhibitor CCR-1 rantagonists are in development. Broad spectrum,
nonselective receptor inhibitors are expected to
have good antiinflammatory and antinociceptive
effect in RA.
Pfizer, Millenium, Berlex/Shering CCR1: CP481715; BX471: none
of these showed therapeutic
efficacy in phase II trials
[54]
Bradykinin B1 and B2 receptork
inhibitor
Strong antiinflammatory effect is expected due to
blockade of bradykinin receptors. Selective
inhibition of the B1 receptor might be
sufficient to achieve analgesia
Several projects known in
pharmaceutical industry
(Fournier, Hoehst, Fujisawa, Winthrop)
No compound entered
clinical trials
[56] No clinical
reference
360
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Vol. 3, No. 3 2006 Drug Discovery Today: Disease Mechanisms | Pain
Tab
le1
(Co
nti
nued
)
Targ
et
Str
ate
gic
ap
pro
ach
tota
rget
Exp
ecte
do
utc
om
eo
fin
terv
en
tio
nat
targ
et
(e.g
.re
du
cti
on
inn
eu
rofi
bri
llary
tan
gle
form
ati
on
)
Wh
ois
wo
rkin
go
nth
eta
rget
Th
era
pie
sin
tria
l(i
fap
plica
ble
)R
efs
Can
nab
ino
id
recep
tors
CB
1lag
onis
tsPer
ipher
aliz
edC
B1
agonis
tshav
ean
tihyp
eral
gesi
c
activi
tyby
blo
ckin
gC
-fiber
s;C
B2
rece
pto
rs
are
invo
lved
inim
mune
resp
onse
s;m
ajor
issu
e:se
par
atio
nof
the
antinoci
ceptive
and
psy
chotr
opic
effe
cts
Bro
adin
tere
stin
phar
mac
eutica
l
indus
try
Clin
ical
tria
lin
MS
show
s
posi
tive
antino
cice
ptive
effe
cts
of
dro
nab
inol
Ane
cdota
lre
port
s[5
7]
aT
um
or
nec
rosi
sfa
ctor
alpha.
bIn
terl
euki
n-1
.cY
clooxyg
enaz
e-1,2
enzy
me.
dN
onst
eroid
alan
ti-inflam
mat
ory
dru
gs.
ePro
stag
landin
-E2.
fPro
stag
landin
E1
rece
pto
r.gA
cid
sensi
ng.
hT
ransi
ent
rece
pto
rpote
ntial
vanill
oid
type
1ch
annel
.iT
etro
doto
xin
-res
ista
nt
sodiu
mch
annel
.jC
hem
oki
ne
rece
pto
r-1.
kB
radyk
inin
1an
d2
rece
pto
rs.
lC
annab
inoid
-1re
cepto
r.
during inflammation associated with arthritis, when
increased osteoclastic activity produces acidic pH [37,38].
In addition to the prostaglandins, many other elements of
the inflammatory mediator cascade contribute to the gen-
eration of acute and chronic joint pain. Elevated levels of CC
Chemokines were found in joints of RA patients (CCL2, CCL3
and CCL5) in parallel with migration of monocytes and T
cells into the synovium [24]. The development of potent
chemokine receptor antagonists, particularly CCR5, promises
reasonable therapeutic potential for the indication of rheu-
matoid arthritis [39].
Cytokines, primarily TNFa, IL-1 and IL-6 are also major
contributors to RA and the generation of joint pain. They
share common signal pathways including the activation of
nuclear factor kappa B (Nf-kB). In addition to their contribu-
tion to acute inflammatory processes, they are also a major
contributor to the chronic inflammatory state and a major
factor in bone resorption and blockade of osteoblast matura-
tion [40]. Together with IL-1 and IL-6, TNFa also contribute to
arthritic pain, particularly during flares [41,42]. Samad et al.
[43] reported that IL-1b-induced induction of COX-2 enzyme
expression contributes to increased nociceptive sensitivity,
whereas TNFa was shown to induce allodynia in neuropathic
models via activation of p38 MAPK in primary afferents [44].
In addition to the above, TNFa also stimulates IL-6 and NOS
synthesis [40], all of which promote inflammation. The pro-
minent role of TNFa and other cytokines was discovered in
various animal models of joint pain, and the effectiveness of
TNFa and IL-1 b blocking therapies in human RA supports
this concept. (Table 1).
Bradykinin B1 and B2 receptor antagonists also have anti-
hyperalgesic effect in experimental arthritis [45]. Bradykinin
B1 and B2 receptors, together with prostaglandin EP1 and EP2
receptors seem to be crucial for the nociceptor and spinal
sensitization cascade [16]. Although bradykinin B2 receptors
are constitutively expressed in nerve terminals of unmyeli-
nated fibers, B1 receptor expression or upregulation is asso-
ciated with inflammatory conditions [45,46]. To date, no
bradykinin antagonists have been evaluated under clinical
conditions, therefore their efficacy in human arthritic pain
remains to be seen.
Summary and conclusions
In summary, the development of joint pain involves noci-
ceptor sensitization and a unique component of silent fiber
activation that together are the major driving force of central
sensitization. The major peripheral contributors of this pro-
cess are inflammatory mediators (cytokines, chemokines,
prostanoids, bradykinin and neurogenic peptides) originat-
ing from non-neuronal and neuronal cells and/or tissues and
their generating enzymes. Peripheral and central endings of
joint nociceptors express receptors for most inflammatory
mediators and through common pathways can sensitize or
www.drugdiscoverytoday.com 361
Drug Discovery Today: Disease Mechanisms | Pain Vol. 3, No. 3 2006
activate TRP, ASIC and Na channels and induce enhance-
ment of transmitter release (SP, NKA, CGRP, NPY, SOM) and
expression of various receptors. These changes produce an
altered nociceptor phenotype, which is characterized by low
threshold activation and enhanced excitability.
The central components develop as a consequence of the
increased peripheral input, and heavily contribute to the
maintenance of the chronic pain state. Although pain asso-
ciated with the early phase of joint disease or with exacer-
bation of RA is considered to be driven by inflammatory
processes, chronic arthritic pain is more likely to have both
inflammatory and neuropathic elements [16]. Increased
transmitter release and receptor expression, altered inhibi-
tory mechanisms and some rewiring in the spinal cord and at
supraspinal nociceptive centers all contribute to the central
component of chronic joint pain.
This complexity of mechanisms explains the difficulties
clinicians face in the treatment of joint pain.
References1 Schaible, H.G. et al. (2002) Mechanisms of pain in arthritis. Ann. N.Y. Acad.
Sci. 966, 343–354
2 Kidd, B.L. (2006) Osteoarthritis and joint pain. Pain 123, 6–9 [Epub]
3 Schaible, H.G. and Grubb, B.D. (1993) Afferent and spinal mechanisms of
joint pain. Pain 55, 5–54
4 Kress, M. and Reeh, P.W. (1996) Chemical excitation and sensitization in
nociceptors. In Neurobiology of Nociceptors (Belmomte, C. and Cervero, F.,
eds), pp. 258–297, Oxford University Press
5 Heppelmann, B. (1997) Anatomy and histology of joint innervation. J.
Peripher. Nerv. Syst. 2, 5–16
6 Macefield, V.G. (2005) Physiological characteristics of low-threshold
mechanoreceptors in joints, muscle and skin in human subjects. Clin. Exp.
Pharmacol. Physiol. 32, 135–144
7 Schaible, H.G. and Schmidt, R.F. (1983) Responses of fine medial articular
nerve afferents to passive movements of knee joints. J. Neurophysiol. 49,
1118–1126
8 Schaible, H.G. and Schmidt, R.F. (1983) Activation of groups III and IV
sensory units in medial articular nerve by local mechanical stimulation of
knee joint. J. Neurophysiol. 49, 35–44
9 Ivanavicius, S.P. et al. (2004) Isolectin B4 binding neurons are not present
in the rat knee joint. Neuroscience 128, 555–560
10 Kuniyoshi, K. et al. (2006) Characteristics of sensory DRG neurons
innervating the wrist joint in rats. Eur. J. Pain [Epub.]
11 Carlton, S.M. and Coggeshall, R.E. (2002) Inflammation-induced
upregulation of neurokinin-1 receptors in rat glabrous skin. Neurosci. Lett.
326, 29–32
12 Lewin, G.R. et al. (1994) Peripheral and central mechanisms of NGF-
induced hyperalgesia. Eur. J. Neurosci. 6, 1903–1912
13 Klede, M. et al. (2003) Central origin of mechanical hyperalgesia. J.
Neurophysiol. 90, 353–359
14 Weidner, C. et al. (1999) Functional attributes discriminating mechano-
insensitive and mechano-responsive C nociceptors in human skin. J.
Neurosci. 19, 10184–10190
15 Orstavik, K. et al. (2003) Pathological C fibers in patients with a chronic
painful condition. Brain 567–578
16 Schaible, H.G. et al. (2006) Pathophysiology and treatment of pain in joint
disease. Adv. Drug Deliv. Revs. 58, 323–342
17 Stein, C. et al. (2001) Peripheral analgesic and anti-inflammatory effects of
opioids. Z. Rheumatol. 60, 416–424
18 Just, S. and Heppelmann, B. (2001) Neuropeptide Y changes the
excitability of fine afferent units in the rat knee joint. Br. J. Pharmacol. 132,
703–708
362 www.drugdiscoverytoday.com
18a Powell, K.J. et al. (2003) Inhibition of neurokinin-1-substance P receptor
and prostanoid activity prevents and reverses the development of
morphine tolerance in vivo and the morphine-induced increase in CGRP
expression in cultured dorsal root ganglion neurons. Eur. J. Neurosci. 18,
1572–1583
19 Bar, K.J. et al. (2004) The expression and localization of somatostatin
receptors in dorsal root ganglion neurons of normal and monoarthritic
rats. Neuroscience 127, 197–206
20 Voilley, N. (2004) Acid-sensing ion channels (ASICs): new targets for the
analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr.
Drug Targets Inflamm. Allergy 3, 71–79
21 Kobayashi, K. et al. (2005) Distinct expression of TRPM8, TRPA1,
and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers
and colocalization with trk receptors. J. Comp. Neurol. 493,
596–606
22 Nagy, I. et al. (2004) The role of the vanilloid receptor (TRPV1) in
physiology and pathology. Eur. J. Pharmacol. 500, 351–369
23 Numazaki, M. and Tominaga, M. (2004) Nociception and TRP channels.
Curr. Drug Targets CNS Neurol. Disord. 3, 479–485
24 Charo, I.F. and Ransohoff, R.M. (2006) The many roles of chemokines
and chemokine receptors in inflammation. New Engl. J. Med. 354,
610–621
25 Jolliffe, V.A. et al. (1995) Assessment of cutaneous sensory and
autonomic axon reflexes in rheumatoid arthritis. Ann. Rheum. Dis. 54,
251–255
26 Deal, C.L. (1991) Treatment of arthritis with topical capsaicin: a double-
blind trial. Clin. Ther. 13, 383–395
27 McCleane, G. (2000) The analgesic efficacy of topical capsaicin is
enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized,
double blind, placebo controlled study. Eur. J. Pain. 4, 355–360
28 Ringkamp, M. et al. (2001) Capsaicin responses in heat-sensitive
and heat-insensitive A-fiber nociceptors. J. Neurosci. 21,
4460–4468
29 Schmidt, R. et al. (1995) Novel classes of responsive and unresponsive C
nociceptors in human skin. J. Neurosci. 15, 333–341
30 Neugebauer, V. et al. (1996) 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,
1095–1109
31 Neugebauer, V. et al. (1995) Inveolvement of substance P and neurokinin-
1 reeceptors in the hyperexcitability of dorsal horn neurons during
development of acute arthritis in rat’s knee joint. J. Neurophysiol. 73, 1574–
1583
32 Urban, L. et al. (1994) Modulation of spinal excitability: Cooperation
between neurokinin and excitatory amino acid transmitters. Trends
Neurosci. 17, 432–438
33 Geba, G.P. et al. (2002) Efficacy of rofecoxib, celecoxib, and
acetaminophen in osteoarthritis of the knee: a randomized trial. J. Am.
Med. Assoc. 287, 64–71
34 Dionne, R.A. et al. (2001) Analgesia and COX-2 inhibition. Clin. Exp.
Rheumatol. 19, 63–70
35 Zhang, Y. et al. (1997) Inhibition of cyclooxygenase-2 rapidly reverses
inflammatory hyperalgesia and prostaglandin E2 production. J. Phamacol.
Exp. Ther. 283, 1069–1075
36 England, S. et al. (1996) PGE2 modulates the tetrodotoxin-resistant
sodium current in neonatal rat dorsal root ganglion neurons via the cyclic
AMP-protein kinase A cascade. J. Physiol. (Lond) 495, 429–440
37 Taylor, P.C. et al. (2000) VEGF release is associated with hypoxia in
inflammatory arthritis. Arthritis Rheum. 43 (Suppl. 9), S296
38 Nagae, M. et al. (2006 Jun 10) Osteoclasts play a part in pain due to the
inflammation adjacent to bone. Bone [Epub ahead of print]
39 Ribeiro, S. and Horuk, R. (2005) The clinical potential of chemokine
receptor antagonists. Pharmacol. and Therap. 107, 44–58
40 Nanes, M.S. (2003) Tumor necrosis factor-a: Molecular and cellular
mechanisms in skeletal pathology. Gene 321, 1–15
41 Hochberg, M.C. et al. (2003) Comparison of the efficacy of the tumor
necrosis alpha blocking agents adalimumab, etanercept and infliximab
Vol. 3, No. 3 2006 Drug Discovery Today: Disease Mechanisms | Pain
when added to methotrexate in patients with active rheumatoid arthritis.
Ann. Rheum. Dis. (suppl. 2), ii13–ii16
42 Hoheisel, U. et al. (2005) Excitatry and modulatory effects of inflammatory
cytokines and neurotrophins on mechanosensitive group IV muscle
afferents in the rat. Pain 114, 168–176
43 Samad, T.A. et al. (2001) Interleukin-1b-mediated induction of COX-2 in
the CNS contributes to inflammatory pain hypersensitivity. Nature 410,
471–475
44 Schaefers, M. et al. (2003) Tumor necrosis factor-a induces mechanical
allodynia after spinal nerve ligation by activation of p38 MAPK in primary
sensory neurons. J. Neurosci. 23, 2517–2521
45 Tonussi, C.R. and Ferreira, S.H. (1997) Bradykinin-induced knee joint
incapacitation involves bradykinin B2 receptor mediated hyperalgesia and
bradykinin B1 receptor mediated nociception. Eur. J. Pharmacol. 326, 61–
65
46 Cruwys, S.C. et al. (1994) The role of bradykinin B1 receptors in the
maintenance of intra articular plasma extravasation in chronic antigen-
induced arthritis. Br. J. Pharmacol. 113, 940–944
47 Danese, S. et al. (2006) Biological therapies for inflammatory bowel
disease: research drives clinics. Mini Revs. In Med. Chem. 6, 771–784
48 Nuki, G. et al. (2002) Long-term safety and maintenance of clinical
improvement following treatment with anakinra (recombinant human
interleukin-1 receptor antagonist) in patients with rheumatoid arthritis:
Extension phase of a randomized, double-blind, placebo-controlled trial.
Arthritis Rheum. 46, 2838–2846
49 Hinz, B. and Brune, K. (2004) Pain and osteoarthritis: new drugs and
mechanisms. Curr. Opin. Rheumatol. 16, 628–633
50 Gibofsky, A. et al. (2003) Comparing the efficacy of cyclooxygenase
2-specific inhibitors in treating osteoarthritis: appropriate trial design
considerations and results of a randomized, placebo-controlled trial.
Arthritis Rheum. 48, 3102–3111
51 Goodwin, J.L. et al. (2005) The use of opioids in the treatment of
osteoarthritis: when, why, and how? Curr. Pain Headache Rep. 9, 390–398
52 Romanovsky, A.A. et al. (2006) Microsomal prostaglandin E synthase-1,
ephrins, and ephrin kinases as suspected therapeutic targets in arthritis:
exposed by ‘‘criminal profiling’’. Ann. N. Y. Acad. Sci. 1069, 183–194
53 Avelino, A. and Cruz, F. (2006) TRPV1 (vanilloid receptor) in the urinary
tract: expression, function and clinical applications. Naunyn Schmiedebergs
Arch. Pharmacol. 373, 287–299 [Epub 2006 May 24]
54 Gladue, R.P. et al. (2003) CP-481,715, a potent and selective CCR1
antagonist with potential therapeutic implications for inflammatory
diseases. J. Biol. Chem. 278, 40473–40480
55 Akopian, A.N. et al. (1999) The tetrodotoxin-resistant sodium channel
SNS has a specialized function in pain pathways. Nat. Neurosci. 2,
541–548
56 Fortin, J.P. and Marceau, F.O. (2006) Advances in the development of
bradykinin receptor ligands. Curr. Top. Med. Chem. 6, 1353–1363
57 Svendsen, K.B. et al. (2004) Does the cannabinoid dronabinol reduce
central pain in multiple sclerosis? Randomised double blind placebo
controlled crossover trial Br. Med. J. 329, 253
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