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Advanced Drug Delivery Reviews 58 (2006) 323 – 342 www.elsevier.com/locate/addr

Pathophysiology and treatment of pain in joint disease B Hans-Georg Schaible a, Martin Schmelz b,*, Irmgard Tegeder c b

a Institut fu¨r Physiologie, Universita¨t Jena, Teichgraben 8, D-07740 Jena, Germany Institut fu¨r Ana¨sthesiologie Mannheim, Theodor Kutzer Ufer 1-3, Universita¨t Heidelberg, D-68167 Mannheim, Germany c pharmacentrum frankfurt, Institut fu¨r Klinische Pharmakologie/ZAFES, Klinikum der Johann Wolfgang Goethe-Universita¨t 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 1.

2.

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 . . . . . .

Central pain pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Central sensitization—increased sensitivity in the central nervous system

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This review is part of the Advanced Drug Delivery Reviews theme issue on bDrug Delivery in Degenerative Joint DiseaseQ, Vol. 58/2, 2006. * Corresponding author. Tel.: +49 621 383 5015; fax: +49 621 383 1463.

E-mail address: martin.schmelz@anaes.ma.uni-heidelberg.de (M. Schmelz).

0169-409X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2006.01.011

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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Peripheral pain system—primary afferent nociceptors

1.1. Peripheral sensitization—local inflammatory changes

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 nociceptors is provided by numerous membrane ion channels and receptors (see peripheral sensitization). Nociceptors can also exert efferent functions in the tissue by releasing neuropeptides (substance P, calcitonin generelated peptide (CGRP)) from their sensory endings.

Thereby they induce vasodilation, plasmaextravasation and other effects, e.g. attraction of macrophages or degranulation of mast cells. The inflammation produced by nociceptors is called neurogenic inflammation [3,4].

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

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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), bradykinin (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 inflammation [2,17–19].

It is conceivable that changes in the expression of ion channels and receptors may contribute to the

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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 stimulation 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 Cfibres 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 inflammatory mediators, and pathological activation of injured nerve fibres by the sympathetic nervous system. After nerve injury the expression of TTXsensitive 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

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firing rates (bursting ectopic discharges) are favoured [24].

Injured axons of primary afferent neurons may be excited by inflammatory mediators, e.g. by bradykinin, 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 segmental motor or vegetative reflex pathways. Ascending axons activate the thalamocortical system that produces the conscious pain sensation (see below). Thus, the pain sensation is just one limited aspect of the underlying nociceptive processes that include encoding 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. Typically these neurons are wide dynamic range neurons.

These cells respond weakly to innocuous stimuli and strongly to noxious stimuli encoding stimulus intensity 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 neurons 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]. Hyperexcitable spinal cord neurons are more susceptible to peripheral inputs and respond, therefore, stronger to stimulation. Central sensitization amplifies the processing 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

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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 hyperalgesia, 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 peripheral 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 thalamocortical 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 afterdischarges 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 tonically 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 stimulation 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 facilitation has also been observed [34], suggesting that the central nervous system can modulate spinal pain processing in either direction.

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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 transmitter 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 neuropeptides support the generation of spinal cord hyperexcitability. Spinal application of antagonists to these receptors attenuates the development of inflammation-mediated hyperexcitability [40–42], probably by a facilitation of glutamatergic synaptic transmission [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 differentiated 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

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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 neuropathic pain [45,46]. Moreover, non-neuronal cells have been shown to be active players in the process of neuronal sensitization: glial cells activated by neuronal 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 relationship between nociception and pain is not tight and the pain does not only reflect tissue damage. Chronic pain may be accompanied by neuroendocrine dysregulation, fatigue, dysphoria, and impaired physical and even mental performance [51]. Multidisciplinary pain research showed that in many cases rather psychological 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 antiinflammatory 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 understanding 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, prostaglandin 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 prostaglandin synthesis (reviewed in Steinmeyer and Kontinnen). Prostaglandins and particularly PGE2 contribute to the sensitization of nociceptors and mechanoreceptors in inflamed tissue including inflamed 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 amplification 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 COXinhibitors depends to a great extent on the inhibition of central PGE2 production and is therefore not directly linked to their anti-inflammatory effects.

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The facilitating PGE2 effects in the dorsal horn are mediated through EP2 receptors expressed in superficial 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 EPreceptors [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 (cyclooxygenase inhibiting NO donators), have been developed 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 modification 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 compared with the parent drugs [84]. NO-NSAIDs have

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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 paracetamol 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 COXinhibition. 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, controlled 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

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effects of injected and endogenous opioids [98,99].

Local injection of opioids into peripheral inflamed tissues causes potent local naloxone-reversible antinociception 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 receptors was doubted until inflammation-attracted immune 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 prolonged 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 inflammatory 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 upregulation of opioid receptors and the release of endogenous opioids from immune cells may lead to novel approaches for the development of peripherally 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 neuroanatomical, neurochemical, and pharmacological features suggesting a crosstalk between both systems and possibly in part complimentary or synergistic functions [128]. The major active constituent of the plant Cannabis sativa (marijuana), delta-9-tetrahydrocannabinol (THC), and a variety of natural and synthetic cannabinoids possess antinociceptive and anti-inflammatory 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 arthritis models [134–137] and prevent cartilage resorption, in part, by inhibiting proteoglycan breakdown and cytokine-induced, iNOS mediated nitric oxide overproduction 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 (endocannabinoids) such as anandamide and 2-arachidonoylglycerol (2-AG) are lipidic messengers derived from arachidonic acid. They are released into the extracellular space and rapidly inactivated by cellular reuptake 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-inflammatory 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 substances. CB-2 receptor activation in the periphery stimulates a release of beta-endorphin from CB-2 positive keratinocytes, leading to peripheral muopioid receptor activation [142]. Together these effects explain the CB-2 receptor mediated inhibition of C-fiber stimulation [143] and show that cannabi-

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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 antinociceptive 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 neuropathic 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 dysregulation 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. The double, 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 InB inhibitor 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 enhances 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 alternative p100/p52 NF-nB pathway. IKK controls its own activity by autophosphorylation that, at a certain level

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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 inflammation 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, particularly 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 recombinant human IL-1 receptor antagonist. In clinical

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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 etanercept 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-chimeric antibodies is reduced compared with infliximab, a chimeric (mouse-human) monoclonal anti-TNFalpha 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 neuropathic 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 inflammation and contributes to pain and hyperalgesia [183– 186]. Recent electrophysiological experiments have strongly suggested the involvement of ASICs (amiloride-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 including 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 hyperexcitability. 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 inhibition 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 Anthopleura 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 elements of the NaV1.8 gene, transgenic mouse lines were generated that express Cre recombinase selectively 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

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in increased excitability of colonic sensory neurons in experimental mouse colitis suggesting a role of these channels in visceral pain [207]. The discrete localization 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 TRPV1deficient mice have shown that this ion channel is essential for thermal hyperalgesia [208]. The activity of TRPV1 is modified by rapidly reversible phosphorylation 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 expression 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 thermosensitive 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

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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 coldsensitive TRPM8 [218], whereas TRPA1 is activated by pungent natural compounds present e.g. in cinnamon oil, mustard oil, and ginger [219]. Bradykinin, 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 hypersensitivity. 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-endothelial 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 terminals, 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 (windup) of nociceptive reflexes [226]. Development of specific bradykinin B1 (and/or B2) antagonists will further reveal potential clinical applications.

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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-, coldand 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.

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