inflamm7

www.elsevier.com/locate/addr

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: [email protected] (M. Schmelz).

mailto:[email protected]

http://dx.doi.org/10.1016/j.addr.2006.01.011

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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 333
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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


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


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


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.


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


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-


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


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


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.


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.


[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


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


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


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.


[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-


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.


[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.


[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.

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