Exp Brain Res (2009) 196:153–162 DOI 10.1007/s00221-009-1782-9
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Joint pain Hans-Georg Schaible · Frank Richter · Andrea Ebersberger · Michael K. Boettger · Horacio Vanegas · Gabriel Natura · Enrique Vazquez · Gisela Segond von Banchet
Received: 23 February 2009 / Accepted: 20 March 2009 / Published online: 11 April 2009 © Springer-Verlag 2009
Abstract Both inXammatory and degenerative diseases of joints are major causes of chronic pain. This overview addresses the clinical problem of joint pain, the nociceptive system of the joint, the mechanisms of peripheral and central sensitization during joint inXammation and long term changes during chronic joint inXammation. While the nature of inXammatory pain is obvious the nature and site of origin of osteoarthritic pain is less clear. However, in both pathological conditions mechanical hyperalgesia is the major pain problem, and indeed, both joint nociceptors and spinal nociceptive neurons with joint input show pronounced sensitization for mechanical stimulation. Molecular mechanisms of mechanical sensitization of joint nociceptors are addressed with an emphasis on cytokines, and molecular mechanisms of central sensitization include data on the role of excitatory amino acids, neuropeptides and spinal prostaglandins. The overview will also address long-term changes of pain-related behavior, response properties of neurons and receptor expression in chronic animal models of arthritis. Keywords Arthritis · Osteoarthritis · Cytokines · Central sensitization · Peripheral sensitization
H.-G. Schaible (&) · F. Richter · A. Ebersberger · M. K. Boettger · H. Vanegas · G. Natura · E. Vazquez · G. Segond von Banchet Institute of Physiology 1/Neurophysiology, University Hospital Jena, Teichgraben 8, 07740 Jena, Germany e-mail:
[email protected]
The clinical problem of joint pain Pain in joints is a major clinical problem (Breivik et al. 2006). At younger age particularly inXammatory diseases such as rheumatoid arthritis are causes of joint pain whereas elder people mainly suVer from pain due to osteoarthritis (OA). Overall, pain from OA seems to be more frequent than pain from inXammatory joint disease (Breivik et al. 2006). However, concerning neuronal mechanisms of joint pain much more information is available on inXammatory joint pain. There are a number of reasons for these discrepancies. First, it is presently ill-deWned under which conditions OA pain occurs. In most cases OA is a slowly progressing disease, and it is unclear at which stage the joint becomes painful. Very often there is a poor correlation between radiological signs (narrow joint space and osteophytes) and the occurrence of pain (Scott 2006). Moreover, the pathogenesis of OA pain is unclear. Recently it was suggested that joint pain results from mild inXammation in joint structures such as the synovial layer. Imaging studies found that painful OA knee joints exhibit more MRI abnormalities than non-painful OA joints. Pathological Wndings in MRI studies were synovial hypertrophy and synovial eVusions as well as subchondral bone marrow edema (which may increase intraosseal pressure) (Felson 2005). These data and the observation of inXammatory cells in the sublining tissue (Scott 2006) may provide evidence that OA pain is evoked by recurring inXammatory episodes. However, this needs to be further substantiated. At later stages capsular Wbrosis and muscle contracture around the joint may contribute to OA pain (Scott 2006). From its nature OA pain is likely to be nociceptive. It is usually localized to the joint with OA but it can be referred (e.g. hip OA may cause knee pain). It varies in intensity and is usually worsened by exercise (weight-bearing, movement)
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and relieved at rest. It is often episodic but may be constantly present in advanced OA. A particular quality is resting pain at night (Scott 2006). Whether this pain is nociceptive or whether a neuropathic component is present is unknown. On the basis of insuYcient clinical data about the pathogenesis and site of OA pain it is diYcult to develop experimental models which are suitable to investigate neuronal mechanisms of OA pain. Models which destruct cartilage within a short time period, or models in which ligaments and menisci are cut thus mimicking the generation of OA following joint injury, are most often used in pain research. These models help to deWne neuronal nociceptive mechanisms resulting from rapid degradation of cartilage. Whether they can explain the pain mechanisms of slowly developing OA is diYcult to answer at the moment. The study of neuronal mechanisms in inXammatory joint pain is easier because the onset of inXammation can be precisely determined and because joint inXammation usually produces pain at early stages. Several experimental models are being used in research on inXammatory joint pain. The injections of kaolin/carrageenan or of carrageenan into the joint cause an acute inXammation which develops within 2–4 h (Schaible and Grubb 1993). In this model identiWed neurons can be recorded throughout the development of inXammation and the generation of hyperexcitability of neurons can directly be monitored. However, because inXammatory joint pain is often chronic, models of chronic inXammation are required for study. Chronic models of inXammation are either unilateral, or they present as polyarthritis. A chronic unilateral inXammation can be induced for example by Freund’s complete adjuvant or by the injection of an antigen into the joint of immunized rats. Examples of chronic forms of polyarthritis are Freund’s complete adjuvant polyarthritis or collagen-induced arthritis (CIA). Some of the models, CIA and antigen-induced arthritis (AIA), are extensively used in rheumatological research because their pathology shows many similarities to human rheumatoid arthritis. The advantage of chronic models is that they exhibit the full spectrum of pathological changes which may be signiWcant for the generation and maintenance of joint pain. For example AIA, an immune-mediated disease dependent on T cells, shows an acute phase and spontaneously progresses into a chronic inXammation. The acute phase of inXammation is characterized by Wbrin exudation and the invasion of granulocytes into the joint. The chronic phase of inXammation is characterized by the inWltration of mononuclear cells, synovial hyperplasia, Wbrosis in the periarticular structures and some cartilage and bone destruction (GriYths 1992; Roth et al. 2005; Segond von Banchet et al. 2000). Patients suVering from inXammation of the joint experience pain during movements in the working range of the
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inXamed joint and gentle pressure, e.g. palpation may elicit pain. Thus joint inXammation is characterized by pronounced mechanical hyperalgesia, and sometimes by persistent pain at rest. This pain may be dull and badly localized (Kellgren 1939; Kellgren and Samuel 1950; Lewis 1938, 1942). Both the acute and chronic experimental models of joint inXammation reliably produce mechanical hyperalgesia (see below), suggesting that they are relevant for the studies on neuronal mechanisms of mechanical hyperalgesia. In some arthritic models thermal hyperalgesia can also be observed, even remote from the inXamed joint which is interpreted as secondary hyperalgesia (Boettger et al. 2008). It is not known if thermal hyperalgesia is important in humans. In the experimental models rats and mice also show signiWcant changes in their locomotor behavior such as limping or shifting weight to the healthy leg (Boettger et al. 2008; Inglis et al. 2007). It needs to be investigated as to whether all changes in locomotor behavior reXect pain.
Overview of the current knowledge on the nociceptive system of the joint Most studies on the nociceptive system are related to cutaneous nociception. By comparison the nociceptive system of the joint has been less extensively addressed (McDougall 2006; Schaible 2006). Pain in the joint and/or other deep tissue is often dull and aching, and poorly localized which is in contrast to cutaneous pain (Lewis 1938). From the diVerent character of cutaneous and deep somatic tissue pain it was proposed very early that the neuronal organization of cutaneous and deep tissue pain is diVerent (Lewis 1938). To date, the neuronal organization of joint pain has not been fully worked out, and thus it is still diYcult to fully explain where the diVerences between cutaneous and joint pain come from. However, this question is relevant because joints and other deep tissues are major sites of clinically relevant pain. An important question is whether the preferential location of chronic pain in deep tissue reXects enhanced vulnerability of the anatomical structures involved or higher incidence of degenerative changes (such as OA) and/or whether the high incidence of pain in deep tissue also depends on the neuronal organization of joint nociception. Innervation of joints Most information is available on the innervation of joints. The joint nerves contain A-, A- and C-Wbers. Corpuscular endings of A-Wbers were identiWed in the ligaments and in the Wbrous capsule. Free nerve endings were identiWed in all structures of the joint except the normal
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cartilage. From all joint structures including ligaments, Wbrous capsule, adipose tissue, meniscus, periosteum and synovial layer, but not cartilage, conscious sensations can be evoked. In awake humans direct stimulation of Wbrous structures with innocuous mechanical stimuli evoked pressure sensations. Pain was elicited when noxious mechanical, thermal and chemical stimuli were applied to the Wbrous structures such as ligaments and Wbrous capsule (Dye et al. 1998; Kellgren and Samuel 1950; Lewis 1942). No pain was elicited by stimulation of cartilage, and stimulation of normal synovial tissue rarely evoked pain (Kellgren and Samuel 1950). In daily life, pain in a normal joint is most commonly elicited by twisting or hitting the joint. Movements in the working range of a normal joint are usually not painful and palpation of a normal joint does not hurt. Recordings from joint aVerents revealed diVerent Wber types in joint nerves concerning their mechanosensitivity. While most Wbers in the A-Wber range show responses to innocuous movements of the joints (Dorn et al. 1991), a large number of A- and C-Wbers show thresholds in the noxious range (rotation of the joint against the resistance of the tissue and intense local pressure). A large group of mainly C-Wbers are so-called silent nociceptors because they do not respond even to noxious mechanical stimuli of the normal joint. They begin to respond to mechanical stimulation during inXammation of the joint. In sum, the joint is equipped with a large number of nerve Wbers which are suitable to encode painful mechanical stimuli (Schaible and Schmidt 1983a, b). However, there are open questions. Electrical stimulation of nerve Wbers in cutaneous nerves allowed investigating which sensations are elicited by stimulation of certain Wber types. Such information is not available for joint nerves. It is unclear which sensations are elicited by electrical stimulation of A-Wbers. Are any conscious pressure sensations evoked? Usually we are not aware of innocuous sensations in the joint. There is not much evidence that these Wbers are involved in the sense of position. Furthermore, does strong activation of thickly myelinated Wbers elicit pain? Some A-Wbers show their highest discharge rates in the noxious range. For example A-Wbers supplying the anterior cruciate ligament show pronounced responses during mechanical stretch which may elicit pain (Krauspe et al. 1992). There are also open questions on Aand C-Wbers. Many A-Wbers and some C-Wbers show weak responses to innocuous stimuli and strong responses to noxious stimuli, and it is unknown whether weak responses of these Wbers in the innocuous range elicit sensations. Moreover, it is unknown whether the selective stimulation of silent nociceptors elicits pain. Finally, could some free nerve endings represent warm or cold receptors giving rise to thermal sensations?
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Spinal cord AVerent Wbers of large joints project to several segments of the spinal cord. Using HRP-labeling projection Welds of knee joint aVerents have been identiWed in the superWcial and the deep dorsal horn (Craig et al. 1988). In general, the localization of Wbers in these laminae matches quite well with the localization of spinal cord cells expressing C-Fos protein, e.g. during urate arthritis in the rat ankle joint (Menetréy et al. 1989). Thus information from the knee joint is processed in the superWcial as well as in the deep dorsal horn of the spinal cord, as also shown in electrophysiological recordings (Grubb et al. 1993; Schaible et al. 1986). Electrophysiological recordings from the spinal cord of anesthetized cats and rats revealed mainly two types of spinal cord neurons with input from the joint (Neugebauer et al. 1993; Schaible et al. 1986, 1987a). Most neurons show convergent inputs from the skin and deep tissue such as joint and adjacent muscles. Often the receptive Weld in the skin is located more distally than the receptive Welds in the deep tissue, thus enabling separate stimulation of receptive Welds in deep tissue and skin. The other type of neurons shows convergent inputs only from deep tissue such as the joint and other deep structures but not from the skin. Most of the neurons with convergent inputs from skin and deep tissue are wide dynamic range neurons which show small responses to innocuous stimuli (for example light to moderate pressure) and strong responses to noxious stimuli applied to the joint (such as noxious pressure or twisting movements). The remaining neurons and most of the neurons with deep input only appear as nociceptive-speciWc neurons which respond only to noxious stimuli applied to the joint and other tissue. Neurons with deep tissue inputs are either ascending tract neurons or local interneurons (Neugebauer et al. 1993; Schaible et al. 1986, 1987a). All open questions on the functional importance of wide dynamic range neurons and nociceptive-speciWc neurons also apply to neurons with joint input (Price et al. 2003). The matter is even more complicated when the convergence of inputs from deep tissue and skin is taken into account. If many neurons receive convergent inputs from skin and deep tissue, how is it possible to experience pain in the deep tissue only? While a substantial number of spinal cord neurons with input from the knee joint are neurons with deep input only, it has not been shown whether these neurons project to supraspinal neurons which are also activated from deep tissue only. In the cat spinal cord neurons were described which are nociceptive-speciWc, are only activated by deep tissue stimulation and have ascending axons in the ventral spinal cord (thus belonging, e.g. to the spinal reticular or spinothalamic tract) (Fields et al. 1977; Maunz et al. 1978; Meyers and Snow 1982). It is thus
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possible that there is a nociceptive labeled line from the joint to supraspinal structures, but it is unknown how information of highly convergent and less convergent neurons is utilized in supraspinal structures. However, this encoding problem applies to all sensory systems. Supraspinal levels In single neuron recordings from anesthetized animals neurons with convergent inputs from skin and deep tissue including the joint were identiWed in lateral, medial and posterior thalamic nuclei, in the somatosensory cortex (Dong et al. 1978; Gautron and Guilbaud 1982; Guilbaud et al. 1977, 1980; Heppelmann et al. 2001; Hutchison et al. 1992, 1994; Lamour et al. 1983a, b, c) and in the amygdala (Han et al. 2005; Ji and Neugebauer 2007; Li and Neugebauer 2004), suggesting that this functional type of neuron is involved at least in some aspects of joint pain at supraspinal levels. However, it has not been deWned in which network of neurons joint pain or other deep tissue pain is generated.
Sensitization of joint nociceptors during inXammation As mentioned, joint inXammation is usually characterized by mechanical hyperalgesia. This is likely to be caused in part by an increase of mechanosensitivity of joint nociceptors. In contrast to cutaneous nociceptors (e.g. Milenkovic et al. 2008), mechanical sensitization of joint nociceptors can easily and reliably be shown. Peripheral sensitization is induced within the Wrst hours after onset of inXammation, and it can persist over weeks in chronic models of inXammation (Guilbaud et al. 1985; Schaible and Schmidt 1985, 1988). Upon development of inXammation A-Wbers show at least a transient increase of their responses to stimulation of the joint (Schaible and Schmidt 1988). Because these Wbers do not exhibit chemosensitivity, the increase of responses could result from swelling and other mechanical factors. Low threshold A-Wbers show increased responses to innocuous and noxious mechanical stimulation of the joint. High threshold A- and C-Wbers show a reduction of their mechanical threshold and enhanced responses to noxious stimuli. Finally, numerous silent nociceptors develop sensitivity for mechanical stimulation of the inXamed joint. This recruitment of Wbers signiWcantly increases the input into the spinal cord (Grigg et al. 1986; Schaible and Schmidt 1985, 1988). These neuronal changes are a plausible explanation for the occurrence of mechanical hyperalgesia or pain of the inXamed joint. Whether they also evoke other sensations such as pressure or stiVness is unknown. It is thought that sensitization of primary aVerent Wbers for mechanical stimuli is produced by inXammatory media-
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tors. This knowledge is based on in vivo experiments in which recordings were made from joint aVerents in situ and in which the responses to mechanical stimuli, mostly movement stimuli, were monitored before and following the application of an inXammatory mediator. The compound of interest was administered to the joint either by close intraarterial injection or by injection of the compound into the joint cavity. The increase of a response may be caused by direct activation of the neuron in the joint but indirect eVects are also possible. Since for many mediators receptors have been identiWed in neurons (mostly in the cell bodies in dorsal root ganglia) it is likely that quick eVects of mediators are produced by activation of receptors in the ending. Sensitization for mechanical stimuli by application of inXammatory mediators could be identiWed in A- as well as in C-Wbers, consistent with the Wnding that both Aand C-Wbers show signiWcant changes of their mechanical responses during inXammation in the joint. A-Wbers did not show changes of their responses to mechanical stimuli following application of a mediator. With the approaches mentioned, a number of mediators have been shown to sensitize joint nociceptors for mechanical stimuli. These include bradykinin, prostaglandin E2, prostaglandin I2, serotonin, substance P, galanin, neuropeptide Y, nociceptin (cf. McDougall 2006; Schaible 2006). Each of these mediators evokes a particular pattern of sensitization. After close intraarterial injection eVects on responses to mechanical stimuli may be quite transient (lasting only minutes) or more persistent (lasting up to an hour). It is thus diYcult to know whether the duration of an eVect is due to the short presence of a mediator or whether the eVect per se is only transient. In our present research (on the eVect of cytokines on responses to mechanical stimuli) we therefore inject compounds into the joint cavity which may be closer to the clinical situation in which mediators are produced locally in the course of the inXammatory process. Using intraarticular injection we have observed remarkable eVects of the cytokine interleukin-6 (IL-6) on the mechanosensitivity of joint aVerents in the rat in situ (Brenn et al. 2007). IL-6 plays an important role in the pathogenesis of rheumatoid arthritis, and its concentration is elevated in the serum and synovial Xuid of arthritic patients (Arvidson et al. 1994; Desgeorges et al. 1997). IL-6 acts on target cells in a two-step process. First IL-6 binds to a speciWc IL-6-binding protein (IL-6R) which is either located at the cell membrane or soluble in the extracellular space (sIL-6R). Second, the IL-6/IL-6R complex binds to the transmembrane protein gp130 which confers the signal to intracellular cascades (Kamimura et al. 2003). When binding to sIL-6R, IL-6 can also stimulate cells that express only the transmembrane subunit gp130 but lack membranebound IL-6R. The sIL-6R concentration is also elevated in
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synovial tissue in rheumatoid arthritis and correlates with the degree of leukocyte inWltration (De Benedetti et al. 1994; Novick et al. 1989). Most DRG neurons express the subunit gp130 suggesting that primary aVerent neurons respond to IL-6 (Obreja et al. 2005; Segond von Banchet et al. 2005). In cultured DRG neurons IL-6 together with its soluble receptor increases heat-induced inward currents showing direct membrane eVects (Obreja et al. 2005). After the injection of 20 ng IL-6 into the knee joint cavity responses of C-Wbers (not of A-Wbers) to innocuous and noxious outward rotation slowly increased, and the increase of responses to noxious outward rotation became signiWcant after about 100 min. The co-administration of IL-6 and its soluble receptor caused a more rapid sensitization and a signiWcant increase in responses to innocuous outward rotation. Co-administration of IL-6 and the soluble form of gp130 (sgp130 which neutralizes IL-6) prevented the IL-6-induced sensitization of joint aVerents showing that the eVects of IL-6 were speciWc (Brenn et al. 2007). No reversal of IL-6-induced mechanical sensitization was observed when sgp130 was administered about 1 h after IL-6 suggesting that the IL-6-induced sensitization was persistent. A similar Wnding was recently reported by Dina et al. (2008) who investigated the role of IL-6 in chronic muscle hyperalgesia. They found that PGE2 has a stronger eVect on the nociceptive threshold 24 h after IL-6 treatment than under control conditions suggesting that IL-6 has a role in “priming” of muscle aVerents. Similar studies are being performed on the role of tumor necrosis factor- (TNF-). In particular neutralization of TNF- with etanercept or inXiximab has signiWcantly improved rheumatoid arthritis in many patients (Feldmann and Maini 2001). Because TNF- is able to evoke eVects in neurons (Sommer and Kress 2004), the question arises whether pain relief by etanercept or inXiximab results from the attenuation of the inXammatory process or from direct eVects at the nerve Wbers. In a study of Inglis et al. (2007) on CIA in mice the neutralization of TNF- reduced both mechanical hyperalgesia (as judged from the testing of withdrawal responses in behavioral experiments) and the inXammatory process. In a study of Boettger et al. (2008) on AIA i.p. application of etanercept and inXiximab reduced mainly mechanical hyperalgesia at the inXamed joint, but the inXammatory process was only weakly attenuated. Collectively these results indicate that at least part of the analgesic eVect of TNF- results from a neuronal eVect. In support for this we found that the intraarticular injection of etanercept into the knee joint of rats at day 3 of AIA signiWcantly reduced the responses of C-Wbers to innocuous and noxious outward rotation of the inXamed knee within 1 h after intraarticular injection. The injection of etanercept into the normal knee joint did not inXuence the responses of
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C-Wbers to innocuous and noxious outward rotation (Boettger et al. 2008). We believe that these data are relevant for inXammatory pain. Whether they are applicable to the problem of OA is unknown. As mentioned, it was suggested that pain during OA may result from mild inXammation. In addition cytokines play a role in OA because activated cartilage produces a number of cytokines (Attur et al. 2002). However, there are signiWcant gaps of knowledge in the understanding of the mechanical sensitization in joint aVerents and aVerents of other tissues. First, the molecular mechanism of transduction of noxious mechanical stimuli is unknown. It is thus impossible to know whether, e.g. joint aVerents (easily sensitized by mechanical stimuli) and cutaneous aVerents (diYcult to sensitize for mechanical stimuli) exhibit diVerences in their molecular structure related to mechanotransduction or whether diVerent mechanosensitivity results from the environment of the sensory ending. In general membrane properties of joint Wbers have only sparsely been addressed (Flake and Gold 2005). Second, our knowledge on the expression of receptors for mediators in joint aVerents and aVerents from other tissues is incomplete. To date we do not know whether nociceptors in diVerent tissues show signiWcant diVerences in their phenotype or whether nociceptors are similar in all tissues. This may again be related to the question of why chronic pain occurs most often in deep tissue and not in the skin.
Central sensitization during inXammation of the joint During development of inXammation in the knee joint ascending and non-ascending spinal nociceptive neurons with knee input are rendered hyperexcitable (Neugebauer et al. 1993; Schaible et al. 1987b). Neurons show a signiWcant increase of their responses to innocuous and noxious mechanical stimulation of the inXamed joint. In high threshold neurons mechanical threshold is lowered into the innocuous range. In addition the neurons show increased responses to stimulation of adjacent, healthy tissues such as the ankle joint, and the receptive Weld may even expand to the paw. The change of responses is even more pronounced in spinalized animals suggesting that descending pathways dampen the generation of hyperexcitability (Neugebauer and Schaible 1990). In fact, during development of inXammation tonic descending inhibition of neurons with input from the inXamed joint is increased (Cervero et al. 1991; Schaible et al. 1991). The pronounced development of hyperexcitability during inXammation in the joint is in agreement with Wndings of Woolf and Wall (1986) and Sluka (2002) who showed that aVerent Wbers from deep
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tissue are particularly capable of inducing central sensitization, compared to cutaneous aVerents. Central sensitization can persist during chronic inXammation. In rats with unilateral arthritis (Grubb et al. 1993) as well as in rats suVering from chronic polyarthritis (Menetréy and Besson 1982) spinal cord neurons with joint input appear on average more sensitive and have expanded receptive Welds. Secondary hyperalgesia due to joint inXammation can last several weeks, and this hypersensitivity is associated with enhanced responses of spinal cord neurons to A and C Wber inputs (Martindale et al. 2007). However, as mentioned, spinal sensitization is counteracted to some extent by inhibitory inXuences. Descending inhibition (Schaible et al. 1991) as well as heterotopic inhibitory inXuences are increased during inXammation (Calvino et al. 1987). Central sensitization is thought to contribute signiWcantly to mechanical hyperalgesia observed in behavioral experiments. Whether central sensitization occurs in the spinal cord of humans is diYcult to assess because recordings cannot be performed in humans. But testing of hyperalgesia in awake humans suggests that this might be the case. When a noxious chemical stimulus, e.g. 6% NaCl, is applied to a muscle, pain is felt in a large area far beyond the stimulation site. Such areas are signiWcantly larger during pathological conditions such as OA (Bajaj et al. 2001). The enlargement of painful areas corresponds to the expansion of receptive Welds of spinal cord neurons suggesting that the described neuronal changes in the spinal cord are the relevant mechanism of secondary hyperalgesia induced by noxious stimulation of deep tissue (Arendt-Nielsen et al. 2000). Although there is evidence for a contribution of central sensitization to mechanical hyperalgesia a number of questions remain to be answered. Is there a threshold for the induction of central sensitization? Does central sensitization persist during long-lasting joint inXammation, e.g. during rheumatoid arthritis? Does central sensitization completely disappear when inXammation is under control? Is persistent central sensitization the reason why some patients are not free of pain after joint replacement? The neuronal mechanisms of inXammation-evoked spinal sensitization and the analysis of the molecular mechanisms will remain a challenge for a long time. There is an increasing number of molecules which are potentially involved in central sensitization, and not only neurons but other cells such as glial cells may be important. The Wnal aim should be to develop a model in which the role of individual factors is clariWed. Important factors of central sensitization are the enhanced intraspinal release of transmitters from sensitized joint aVerents as well as an increase of excitability of postsynaptic neurons (Schaible 2006; Schaible et al. 2006). Recently long-term potentiation was
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demonstrated in the superWcial dorsal horn suggesting that “learning-like” mechanisms may also be at work (Sandkuehler 2000). Irrespective of the precise mechanisms the involvement of several transmitters and receptors in the induction and maintenance of central sensitization during joint inXammation has been identiWed. In the kaolin/carrageenan model excitatory amino acids as well as the neuropeptides substance P, neurokinin A and CGRP are involved. Spinal application of antagonists at the AMPA receptor, NMDA receptor, metabotropic glutamate receptors, the neurokinin-1 receptor, the neurokinin-2 receptor and the CGRP receptor attenuated the development of hyperexcitability, when given during development of inXammation, and the antagonists partly reversed central sensitization when they were applied once inXammation and spinal hyperexcitability had developed (Schaible 2006; Schaible et al. 2006). As a further indicator of spinal release of substance P during arthritis, movements of an arthritic joint was found to induce internalization of the neurokinin 1 receptor (Sharif Naeini et al. 2005). However, it is important to point out that the antagonists at neuropeptide receptors are less antinociceptive than antagonists at glutamate receptors. Spinal prostaglandins (PGs) are also involved. During inXammation in the joint, there is a tonic release of PGE2 within the dorsal and ventral horn. This is likely to result from an upregulation of spinal COX-2 that is already increased at 3 h after induction of knee joint inXammation (Ebersberger et al. 1999). The application of PGE2 (Vasquez et al. 2001) and of agonists at the EP1, EP2, and EP4 receptor (Bär et al. 2004a) to the spinal cord surface facilitated the responses of spinal cord neurons to mechanical stimulation of the joint like during peripheral inXammation, suggesting that PGE2 contributes to central sensitization. In support for this, spinal application of the COX inhibitor indomethacin attenuated the development of hyperexcitability. However, indomethacin did not reduce the enhanced responses of spinal cord neurons to mechanical stimulation when inXammation of the joint and spinal hyperexcitability were established. We believe, therefore, that spinal PGs are mainly involved in the generation of inXammation-evoked spinal hyperexcitability and less in its maintenance (Vasquez et al. 2001). In this context the transcription factor nuclear factor-B (NF-B) plays a role, because the activation of COX-2 depends on the activation of NF-B (Barnes and Karin 1997; Chen et al. 2003; Lee et al. 2004; Tegeder et al. 2004). NF-B is controlled mainly by IB proteins which keep NF-B in the cytoplasm and inhibit its DNA binding activity. Spinal application of a speciWc IB kinase (IKK) inhibitor prevented the generation of spinal hyperexcitability during developing joint inXammation but did not reduce the responses of neurons to mechanical stimulation when
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peripheral inXammation and spinal hyperexcitability was established (Ebersberger et al. 2006). The role of spinal PGs is likely to be much more complicated. When spinal hyperexcitability was established only the EP1 receptor agonist further increased responses to mechanical stimulation of the inXamed knee whereas the EP2 and the EP4 agonists did not inXuence neuronal responses. By contrast, spinal application of an agonist at the EP3 receptor had no inXuence on neuronal responses when the joint was normal but reduced the responses to mechanical stimulation of the knee when it was spinally applied during established inXammation (Bär et al. 2004a). Thus, the status of the spinal cord may determine which EP receptor agonist causes an eVect upon spinal application. Furthermore, another major prostaglandin in the central nervous system, namely PGD2 (Willingale et al. 1997) may come into play. During joint inXammation PGD2 dosedependently reduced responses of spinal cord neurons to stimulation of the inXamed knee joint, and spinal application of an antagonist at the DP1 receptor increased responses to stimulation of the inXamed knee (TelleriaDiaz et al. 2008). The opposite eVects of PGE2 and PGD2 on the responses of spinal cord neurons could be directly shown (Telleria-Diaz et al. 2008). The reduction of enhanced responses by PGD2 may represent a neuroprotective eVect (Grill et al. 2008; Liang et al. 2005). The inhibitory action may be caused by activation of DP1 receptors on inhibitory spinal interneurons (Minami et al. 1997).
Long-term changes during persistent joint inXammation Many inXammatory joint diseases and OA in particular are chronic painful disorders. It is an intriguing question, therefore, “how chronic” useful experimental models should be in order to gather data which are relevant for long-lasting articular pain in humans. In most experimental models most pronounced eVects on behavior are observed in the Wrst (acute) stages of inXammation, but for the understanding of chronic pain the more subtle changes at later stages may be more important. The demonstration of peripheral and central sensitization for a duration of several weeks (see above) might indicate that these processes are important over long periods. This does not necessarily imply that the molecular mechanisms of peripheral and central sensitization are the same during the whole time. Furthermore, the disease process may signiWcantly change over time and diVerent causes for pain may arise when tissue is more and more destructed (see Wrst section). In order to understand chronic pain much more work at chronic stages is necessary both in experimental models and in humans.
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On the basis of the current knowledge, several questions should be addressed. Some reports indicate that the innervation pattern of joints may change during inXammation. However, while some authors reported a loss of sensory Wbers in chronically inXamed joints, others reported rather a loss of sympathetic innervation (cf. Schaible and Grubb 1993; Straub and Cutolo 2001). Thus changes of innervation may occur but their implications for joint pain have not been suYciently addressed. Changes of innervation may not only be important for the aspect of pain. Both aVerent and sympathetic Wbers can inXuence the disease processes in the tissue, and it is therefore an intriguing question whether functional and bidirectional loops are involved in chronic pain. Within the nervous system changes of receptor expression and of mediator synthesis have been observed upon long-lasting peripheral inXammation. In the AIA model we have noted, e.g. a reduction of the proportion of dorsal root ganglion neurons which express the somatostatin receptor sst2a, but other sst receptors such as the sst2b receptor were not altered (Bär et al. 2004b). The downregulation of the sst2a receptor might indicate that neurons can be less inhibited by somatostatin during AIA (Carlton et al. 2001; Heppelmann and Pawlak 1997, 1999) but the stable expression of the sst2b receptor might compensate for that. Thus there is a rationale for considering somatostatin receptor agonists for the treatment of chronic inXammatory pain (Helyes et al. 2004). In the same model the expression of the TRPV1 receptor in dorsal root ganglia did not change (Bär et al. 2004c) which was unexpected because upregulation of TRPV1 receptors was found in other models of inXammation (Amaya et al. 2003; Carlton and Coggeshall 2001; Ji et al. 2002; but see Zhou et al. 2003). The role of TRPV1 receptors in joint pain is unclear, and it should be noted that mechanical, not thermal hyperalgesia is the major problem of joint diseases. The TNF receptors TNFR1 and TNFR2 (Boettger et al. 2008) did also not change in DRGs during the course of AIA. The stable expression of TNF receptors could be an important basis for TNF- eVects at all stages of inXammation. Taken together data on arthritic models show some long-term changes in the nervous system during chronic joint disease but the total pattern of changes and their functional consequences must be better understood.
Conclusions The gap between clinical pain and pain research is becoming smaller. Further progress will depend to some extent on the ability of researchers of diVerent disciplines to work together. Although pain itself is an interesting neurobiological problem per se it is still a symptom of underlying diseases, at least in many cases. We believe, therefore, that
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one can learn a lot from experimental models provided that they are reasonably close to the pathological processes which occur in humans. The epidemiological data on the frequency of joint pain show that articular pain is a challenge for pain research.
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