Mechanisms underlying joint pain

MECHANISMS

DRUG DISCOVERY

TODAY

DISEASE

Drug Discovery Today: Disease Mechanisms Vol. 3, No. 3 2006

Editors-in-Chief

Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA

Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA

Pain

Mechanisms underlying joint painIstvan Nagy1, Katalin V. Lukacs2, Laszlo Urban3,*1Department of Anaesthesiology and Intensive Care, Imperial College London, London, UK2School of Medicine, Chelsea and Westminster Hospital, London, UK3Preclinical Compound Profiling, Lead Discovery Center, Discovery Technologies, Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue,

Cambridge, MA 02139, USA

Joint pain is associated with injury, inflammation of the

joint and severe remodeling of the subchondrial bone.

The leading reason of articular pain is osteo- and rheu-

matoid arthritis. The most important component of

joint pain is sensitization of high threshold nociceptors,

which release neuropeptides, express excitatory recep-

tors and ion channels. Ongoing hyperexcitability of

nociceptors results in permanent CNS changes con-

tributing to the maintenance of chronic pain.

*Corresponding author: L. Urban ([email protected])

1740-6765/$ � 2006 Published by Elsevier Ltd. DOI: 10.1016/j.ddmec.2006.10.002

Section Editors:Frank Porreca – University of Arizona, Tucson, USAMichael Ossipov – University of Arizona, Tucson, USA

ents, because they are activated only after sensitization by

Introduction

One of the most frequent chronic pain sensations people

experience is associated with pathological conditions of the

joints. Although injuries, infections and systemic diseases

could produce short-term arthralgias, the most common

reasons for joint pain are osteoarthritis (OA) and rheumatoid

arthritis (RA). About 10% of the world’s population over 60

suffer from OA, and about 1% are affected by RA. In contrast

to acute pain caused by injury, pain associated with OA and

RA does not promote restoration of function. Instead, it

worsens the long-term functional outcome and quality of

life. Current therapies for OA or RA are often inadequate and

carry considerable adverse reactions. The development of

new analgesics is hampered by the lack of understanding

the complex pathways involved in the development and

maintenance of these diseases.

Although, joint pain has both peripheral and central

(spinal and brain) components [1,2], the present review

concentrates on the peripheral mechanisms, because they

are pivotal in the initiation and maintenance of pain in OA

and RA.

Sensory innervation of joints

Fibers innervating joints generally respond to mechanical

stimuli, but some are called ‘silent’ polymodal primary affer-

inflammatory agents. Specific nociceptors, which innervate

the joint, belong to the class of thinly myelinated (Ad) or to

unmyelinated I fibers. They can be activated by noxious

mechanical stimuli, such as overstretching the joint, but

some of them form the class of polymodal sensory primary

afferents, which in addition to mechanical stimuli responds

to noxious thermal- and chemical stimuli. They express

various types of receptors and ion channels, which are essen-

tial for neurotransduction. A subpopulation produces neu-

ropeptides and other neurogenic substances, which are

released both in the spinal cord and to the joint tissue.

The central release couples nociceptors with spinal neurones,

whereas the peripheral release induces neurogenic inflamma-

tion, such as plasma protein extravasation, vasodilation and

accumulation of immune cells in the joint. The special group

of silent fibers is not activated even by noxious stimuli under

physiological conditions; however, they can be sensitized

and start responding to non-noxious stimuli during inflam-

mation [3,4].

The innervationof the joint ishighly specific: (1)myelinated

Aa-, Ab-, thin myelinated Ad- and the unmyelinated C-sensory

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http://dx.doi.org/10.1016/j.ddmec.2006.10.002

Drug Discovery Today: Disease Mechanisms | Pain Vol. 3, No. 3 2006

fibers contribute to the sensory innervation of the capsule,

ligaments, periosteum, subchondral bone and menisci; (2)

only C-fibers innervate the synovial membrane and (3) the

articular cartilage has no nerve supply [5,6]. It is estimated that

about 80% of the total number of sensory fibers supplying the

joints belongs to the unmyelinated C primary afferents [3,7,8].

About 15–35% of the small caliber fibers are peptidergic, con-

taining substance P (SP) and calcitonin-gene related peptide

(CGRP) [9,10,11].

In general, while Aa, Ab and a proportion of Ad fibers can

be activated by innocuous light pressure and stretch, these

fibers do not contribute to the generation of joint pain; their

main function is ‘proprioception’. Large proportion of the Ad-

fibers and virtually all C-fibers are solely responsive to nox-

ious stimuli. The responsiveness of these fibers to mechan-

ical, chemical and thermal stimuli can be enhanced by the

induction of receptor and ion channel expression. Nerve

Growth Factor (NGF) is one of the major factors that can

produce such effects [12]. The increased responsiveness,

called sensitization is evident both by reduced activation

threshold to the level of innocuous stimuli and increased

impulse generation of the fibers [4]. NGF, however, is only

one factor that produces sensitization. Many inflammatory

mediators, such as prostaglandins and bradykinin have simi-

lar effects. They can also stimulate increased neuropeptide

production in the peptidergic fibers. The decreased threshold

and the enhanced neuropeptide production cause hypersen-

sitivity of the nociceptive system during inflammation.

The sensitization phenomenon is the most striking in

silent fibers [13,14]. Silent fibers account at least for the third

of the C-fiber population [3]. Although our knowledge about

silent fibers innervating the joint is relatively limited, it is

well established that cutaneous fibers with similar modalities

play a strong role in neurogenic inflammation in humans

[14,15].

Molecular characteristics of C-fibers innervating joints

C-fibers, including the peptidergic fibers express a series of

membrane molecules that can be activated by various che-

mical and physical stimuli. The modality of pain experienced

in joints affected by OA and RA is predominantly mechanical,

it develops within the normal moving range of the joint and

is generally described as throbbing or stabbing. The molecular

characteristics of the joint fibers associated with the above

sensations is not completely understood, however, recent

studies suggest that a broad variety of receptor and channel

proteins expressed on joint nociceptors can be the transdu-

cers. For direct activation by inflammatory mediators, bra-

dykinin, B1 and B2 receptors, prostaglandin EP1 and EP2 and

histamine receptors are expressed in joint nociceptors [16].

Primary afferents have large populations of neurotransmitter

receptors, such as muscarinic, P2X, adrenergic, opioid [17],

cannabinoid (CB1) and 5-HT, which provide plenty of oppor-

358 www.drugdiscoverytoday.com

tunities for direct modulation of excitability. Most peptider-

gic nociceptors express receptors for neurokinins, such as

substance P (NK-1 receptors), neuropeptide Y (NPY, Y1,

Y2); [18], somatostatin (SOM-1,2,3,4) and calcitonin gene-

related peptide (CGRP) [18a]. In general, opioids, somatos-

tatin and cannabinoids act as inhibitors of nociceptor

activation, however their up- or downregulation during

inflammation defines their hyperalgesic potency. It has been

shown recently, that all four SOM receptor subtypes are

present in joint fibers and SOM-2 is downregulated in mono-

arthritis leading to reduction of inhibition of primary afferent

activation [19].

Specific ion channels, such as members of the acid sensing

ion channels (ASICs) and transient receptor potential (TRP)

superfamily provide sites for pH and heat sensitization and

activation. ASICs are expressed in C fibers, activated by acidic

pH; however, recent studies revealed that they are also direct

targets of some NSAIDs [20]. The TRPV1 receptor is activated

by capsaicin, protons and noxious heat, whereas other mem-

bers of the super family (TRPV2,3,4,8 and TRPA1) are likely to

be involved only in thermal nociception [21]. TRPV8 is

expressed in large and small caliber fibers, however TRPV1

expression is largely restricted to C fibers [22]. Interestingly,

those fibers that express these two TRPs have also tyrosine

kinase (trk) receptors, which are activated by NGF [23]. Both

trk and cytokine receptor activation can modulate the phe-

notype of the fibers and contribute to the sensitization of

silent fibers [12,24].

Other, voltage gated ion channels, such as K+, Na+ and Ca2+

channels also contribute to the activation of primary affer-

ents. TTX-insensitive Na channels play a particularly promi-

nent role in nociceptor function (see later).

Mechanisms involved in the development of joint pain

Joint pain in arthritis is characterized by spontaneous pain in

addition to hyperalgesia and allodynia (pain sensation

induced by non-noxious stimuli, such as touch), which are

considered the consequences of both peripheral and central

sensitization [1,3]. RA-affected joints and the surrounding

tissues show increased sensitivity to noxious stimuli [25].

Activation of these sensitized fibers, through triggering a

series of changes in the responsiveness of neurons in the

central nervous system, results in pain sensation. Desensiti-

zation or degeneration of the sensitized fibers by capsaicin

results in reduced pain [26,27]. This is one of many observa-

tions which supports our present knowledge, that pain asso-

ciated with arthritis is largely due to sensitization of the

primary afferents, in particular of nociceptors innervating

the joint. As a consequence, the activation threshold of the

polymodal nociceptors will be reduced and fibers will be

activated by non-noxious stimuli, such as gentle move within

the normal range of the joint or light touch (mechanical

allodynia). Also, inflammatory mediators, pH changes and

Vol. 3, No. 3 2006 Drug Discovery Today: Disease Mechanisms | Pain

Figure 1. Peripheral and central components contribute to the development and maintenance of chronic joint pain. Both non-neuronal and neuronal

elements play an important role in peripheral sensitization of nociceptors. Central components reflect on increased transmitter release, upregulation of

receptor population and rearrangement of synaptic connections.

moderate heat stimuli will activate these fibers under the

inflammatory conditions. In addition to the sensitization of

the regular high threshold polymodal nociceptors, the silent

fibers will be sensitized by inflammatory mediators as well. A

special feature of the sensitized silent fibers is the long lasting

firing to the application of capsaicin [28]. The ‘awakening’ of

the silent fiber population has an important contribution to

the initiation of spinal sensitization [13,29], which is a major

component of chronic pain states.

Ongoing activity in these and other high threshold poly-

modal nociceptors will create a high level of spinal dorsal

horn activity by the excessive release of transmitters, includ-

ing glutamate and neuropeptides, such CGRP and substance

P [30,31]. One of the major elements of central sensitization is

NMDA receptor activation, which is, at least partially,

enhanced by the release of the above mentioned neuropep-

tides [32]. In addition to the high level of neurotransmitter

release, there is evidence for upregulation of various neuro-

transmitter receptors and enzymes in the dorsal root ganglia

(DRG) owing to the increased activity and by direct effects of

inflammatory mediators [16]. For summary of peripheral and

central components of chronic joint pain (Fig. 1).

Peripheral activation and sensitization of joint

afferents

At present, the most broadly used anti-inflammatory and

antihyperalgesic agents for attenuation of joint pain are

NSAIDs and selective COX-2 enzyme inhibitors. Inhibition

of the COX-1,2 enzymes blocks prostaglandin synthesis,

particularly the production of PGE-2 which is a powerful

inflammatory mediator and can sensitize nociceptors inner-

vating joints [16]. COX-1 is constitutively expressed, whereas

COX-2 is an inducible form of the enzyme that becomes a

prominent player in inflammatory conditions [33]. Inhibi-

tion of either of the two COX enzymes or the separate

blockade of COX-2 produces significant antihyperalgesic

activity [34,35].

Although the pain-inducing mechanism of PGE2 is not

fully understood, there is clear evidence that it can directly

enhance the excitability of the TTX-resistant Na channel,

expressed on the unmyelinated fibers [36]. It is anticipated

that the expression of COX enzymes is not only upregulated

during arthritis in the inflamed joint but also in the spinal

cord. Blockade of the spinal enzyme seems to be important

for the antihyperalgesic effects of NSAIDs and selective COX-

2 inhibitors [16]. However, NSAIDs and COX-2 inhibitors

have largely symptomatic effects and do not cure arthritis or

any other joint disease associated with pain. PGE2 is only one

of the many inflammatory mediators contributing to the

pathogenesis of arthritis and joint pain. Individual blockade

of prostaglandin receptors, therefore, may not result in a

strong antihyperalgesic activity. On the contrary, as men-

tioned in the previous chapter, recent studies found that

some NSAIDs block ASIC channels directly, which could

explain their enhanced antihyperalgesic and analgesic activ-

ity [20]. This finding seems to make lots of sense as the

different degree of analgesic effect of various NSAIDs were

difficult to explain. ASIC channel activation is very likely

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Table 1. Targets and related therapies for joint pain

Target Strategic approach

to target

Expected outcome of intervention at target

(e.g. reduction in neurofibrillary tangle formation)

Who is working on the target Therapies in trial (if applicable) Refs

TNFaa Soluble TNF-receptor

fusion protein

Reduction in disease activity RA, including pain.

Clinical trials show positive effect when

used with methotrexate.

Broad interest: Bayer, Wyeth, Amgen,

Abbott Labs, Celltech

Clinical trials: adalimumab;

etanercept; infliximab

[41,47]

IL-1b Recombinant human IL-1

antagonist

Reduction in disease activity RA, including pain Academia and several pharmaceutical

and biotech companies

Clinical trials: anakinra [43,48]

COX-1,2c Nonselective inhibitors:

NSAIDsd

Effects at both peripheral and central sites;

significant antiinflammatory effect;

antihyperalgesic effects vary between

different compounds.

More than 20 NSAIDs are registered

for clinical use

NSAIDs are broadly used in

arthritic pain syndromes

[49]

COX-2 Selective COX-2

inhibitors

Effects at both peripheral and central sites;

significant antiinflammatory and

antihyperalgesic effects due to inhibition of

prostaglandin synthesis;

less GI activity than seen with NSAIDs

Broad interest by many

pharmaceutical companies (Pfizer,

Merck, Novartis)

Coxibs are in the clinics: Celebrex,

Prexige, (Vioxx withdrawn)

[49,50]

Opiates Peripheral m and k

opioid receptors

Opioid recepots are expressed on primary afferents

and immune cells in the periphery;

peripheralized selective agonists could

produce antinociception without CNS effects

Broad interest in pharmaceutical

industry and clinical applications

Promising clinical studies with

topical use of morphine

[17,51]

PGE2e Receptor inhibition EP1f receptor inhibitors might be useful

antiinflammatory and analgesic

No specific inhibitors publishedfor

clinical use

No clinical data No clinical reference

[52]

ASICg Channel blocker Expected analgesic activity; COX inhibitors

have a direct effect on ASIC channels

Relatively new target, projects are

at early phase of drug discovery

Psalmotoxin, APETx2: not in

clinical trials

No clinical reference

TRPV1h Channel blocker or

modulator

Expected strong inhibitory effect on nociceptors;

Block of transduction and impulse

propagation in C fibers could produce

highly selective analgesic effects

Many pharmaceutical companies

are working on this target

(e.g., GSK, Merck)

No small molecule available

for clinical trials; natural

products capsaicin and

resiniferatoxin are used topically

[53]

TTX-resistant

Na channeliChannel blocker Inhibitors are expected to have a selective blocking

effect on nociceptors with good analgesic activity

Broad interest in academia and

pharmaceutical industry;

difficult target

No small molecule available

for clinical trials

No clinical reference

[55]

CCR-1j Receptor inhibitor CCR-1 rantagonists are in development. Broad spectrum,

nonselective receptor inhibitors are expected to

have good antiinflammatory and antinociceptive

effect in RA.

Pfizer, Millenium, Berlex/Shering CCR1: CP481715; BX471: none

of these showed therapeutic

efficacy in phase II trials

[54]

Bradykinin B1 and B2 receptork

inhibitor

Strong antiinflammatory effect is expected due to

blockade of bradykinin receptors. Selective

inhibition of the B1 receptor might be

sufficient to achieve analgesia

Several projects known in

pharmaceutical industry

(Fournier, Hoehst, Fujisawa, Winthrop)

No compound entered

clinical trials

[56] No clinical

reference

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during inflammation associated with arthritis, when

increased osteoclastic activity produces acidic pH [37,38].

In addition to the prostaglandins, many other elements of

the inflammatory mediator cascade contribute to the gen-

eration of acute and chronic joint pain. Elevated levels of CC

Chemokines were found in joints of RA patients (CCL2, CCL3

and CCL5) in parallel with migration of monocytes and T

cells into the synovium [24]. The development of potent

chemokine receptor antagonists, particularly CCR5, promises

reasonable therapeutic potential for the indication of rheu-

matoid arthritis [39].

Cytokines, primarily TNFa, IL-1 and IL-6 are also major

contributors to RA and the generation of joint pain. They

share common signal pathways including the activation of

nuclear factor kappa B (Nf-kB). In addition to their contribu-

tion to acute inflammatory processes, they are also a major

contributor to the chronic inflammatory state and a major

factor in bone resorption and blockade of osteoblast matura-

tion [40]. Together with IL-1 and IL-6, TNFa also contribute to

arthritic pain, particularly during flares [41,42]. Samad et al.

[43] reported that IL-1b-induced induction of COX-2 enzyme

expression contributes to increased nociceptive sensitivity,

whereas TNFa was shown to induce allodynia in neuropathic

models via activation of p38 MAPK in primary afferents [44].

In addition to the above, TNFa also stimulates IL-6 and NOS

synthesis [40], all of which promote inflammation. The pro-

minent role of TNFa and other cytokines was discovered in

various animal models of joint pain, and the effectiveness of

TNFa and IL-1 b blocking therapies in human RA supports

this concept. (Table 1).

Bradykinin B1 and B2 receptor antagonists also have anti-

hyperalgesic effect in experimental arthritis [45]. Bradykinin

B1 and B2 receptors, together with prostaglandin EP1 and EP2

receptors seem to be crucial for the nociceptor and spinal

sensitization cascade [16]. Although bradykinin B2 receptors

are constitutively expressed in nerve terminals of unmyeli-

nated fibers, B1 receptor expression or upregulation is asso-

ciated with inflammatory conditions [45,46]. To date, no

bradykinin antagonists have been evaluated under clinical

conditions, therefore their efficacy in human arthritic pain

remains to be seen.

Summary and conclusions

In summary, the development of joint pain involves noci-

ceptor sensitization and a unique component of silent fiber

activation that together are the major driving force of central

sensitization. The major peripheral contributors of this pro-

cess are inflammatory mediators (cytokines, chemokines,

prostanoids, bradykinin and neurogenic peptides) originat-

ing from non-neuronal and neuronal cells and/or tissues and

their generating enzymes. Peripheral and central endings of

joint nociceptors express receptors for most inflammatory

mediators and through common pathways can sensitize or


Drug Discovery Today: Disease Mechanisms | Pain Vol. 3, No. 3 2006

activate TRP, ASIC and Na channels and induce enhance-

ment of transmitter release (SP, NKA, CGRP, NPY, SOM) and

expression of various receptors. These changes produce an

altered nociceptor phenotype, which is characterized by low

threshold activation and enhanced excitability.

The central components develop as a consequence of the

increased peripheral input, and heavily contribute to the

maintenance of the chronic pain state. Although pain asso-

ciated with the early phase of joint disease or with exacer-

bation of RA is considered to be driven by inflammatory

processes, chronic arthritic pain is more likely to have both

inflammatory and neuropathic elements [16]. Increased

transmitter release and receptor expression, altered inhibi-

tory mechanisms and some rewiring in the spinal cord and at

supraspinal nociceptive centers all contribute to the central

component of chronic joint pain.

This complexity of mechanisms explains the difficulties

clinicians face in the treatment of joint pain.

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Mechanisms underlying joint pain