Skip Navigation


Rheumatology Advance Access originally published online on October 25, 2005
Rheumatology 2006 45(3):295-302; doi:10.1093/rheumatology/kei156
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/3/295    most recent
kei156v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bileviciute-Ljungar, I.
Right arrow Articles by Spetea, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bileviciute-Ljungar, I.
Right arrow Articles by Spetea, M.
Related Collections
Right arrow Experimental Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-inflammatory effects of contralateral administration of the {kappa}-opioid agonist U-50,488H in rats with unilaterally induced adjuvant arthritis

I. Bileviciute-Ljungar1,5, T. Saxne3 and M. Spetea2,4

1 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden, 2 Department of Surgical Sciences, Section of Orthopaedics, Karolinska Institutet, Orthopaedic Research Laboratory M3:02, Karolinska Hospital, Stockholm, Sweden, 3 Department of Rheumatology, Lund University Hospital, Lund, Sweden and 4 Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria. 5 Present address: University Clinic of Rehabilitation Medicine Stockholm, Danderyd Hospital, Building 32, 182 88 Stockholm, Sweden.

Correspondence to: I. Bileviciute-Ljungar, University Clinic of Rehabilitation Medicine Stockholm, Danderyd Hospital, Building 32, 182 88 Stockholm, Sweden. E-mail: indre.ljungar{at}ds.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Objective. The effect of repeated contralateral treatment with the {kappa}-opioid receptor agonist U-50,488H {trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methanesulphonate} was investigated in rats with unilaterally induced adjuvant arthritis.

Methods. Arthritis was induced by injection of Mycobacterium butyricum into the right hindpaw. Inflammatory parameters, nociceptive behaviour and cartilage turnover were evaluated up to 21 days after induction of arthritis.

Results. Contralateral treatment with 0.3 mg U-50,488H into the left hindpaw twice per week reduced the hindpaw oedema, ankle joint inflammation, pain behaviour to mechanical stimuli and severity score of inflammation in the hindpaws of both sides as well as the systemic spread of inflammation to other areas, e.g. tail and/or forepaws, compared with saline-treated animals. Moreover, a significant decrease in the levels of cartilage oligomeric matrix protein was found in animals treated with U-50,488H, suggesting reduction of cartilage damage. The anti-inflammatory and chondroprotective effects of U-50,488H were abolished by administration of the peripheral opioid receptor antagonist naloxone methiodide.

Conclusions. This is the first report demonstrating that repeated contralateral administration of a {kappa}-opioid receptor agonist diminishes the development of a symmetrical joint disorder.

KEY WORDS: Contralateral treatment, {kappa}-Opioid agonist, U-50, 488H, Cartilage oligomeric matrix protein, Adjuvant arthritis, Rats


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The presence of symmetrical clinical symptoms in chronic inflammatory and painful disorders is well known. A clear example is the symmetrical involvement of peripheral joints in rheumatoid arthritis, which is an important criterion for the characterization of this disease. Already in 1985, Levine and collaborators hypothesized that the nervous system might provide an explanation for the symmetry found in rheumatoid arthritis [1]. This was further elaborated by Kidd and colleagues, who suggested that a symmetrical neurogenic response is a part of host defence mechanisms [2].

Recently, we have reported a new approach to the investigation of the bilateral responses after contralateral drug treatment in unilateral inflammatory pain and peripheral nerve injury [3–6]. A single contralateral but non-systemic administration of a low dose of a drug which inhibits nerve activity (e.g. the local anaesthetic xylocaine or the {kappa}-opioid receptor agonist U-50,488H) has been shown to attenuate nociceptive behaviour for up to 24 h in a dose-dependent manner in acute carrageenan-induced hindpaw inflammation in the rat [3, 4]. Complete sciatic nerve section on the contralateral side [3, 4] or intrathecal disruption of the spinal cord mechanisms with saline [3] abolished the antinociceptive effect of the contralateral drug treatment. Furthermore, these drugs administered contralaterally to rats with peripheral unilateral neuropathy (chronic constriction of the sciatic nerve) also reduced pain-related behaviour for several days after injection [5, 6].

In the present study, we investigated the effect of contralateral administration of the {kappa}-opioid receptor agonist U-50,488H on the development of adjuvant-induced arthritis in rats. The aim of this work was to assess the importance of the contralateral nerve input in the development of symmetrical disease. We assumed that the effective therapeutic dose of U-50,488H (0.3 mg) used for the contralateral treatment in acute carrageenan-induced inflammation would also be applicable in the adjuvant arthritis model, since this particular dose has been shown not to induce systemic effects [4, 5].


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experimental protocol for animal studies
Experiments were performed on 38 freely moving female albino Lewis rats (M&B, Ry Denmark) weighing 182 ± 2 g on the experimental day, with free access to food and water according to the Karolinska Institute protocol. Experimental procedures were approved by the Ethics Committee for Animal Research (North Stockholm, Sweden).

All rats were accustomed to the testing conditions six times daily for 3 days. On the experimental day (day 0), the basal pretreatment values of hindpaw volumes, diameters of ankles, and hindpaw withdrawal latency (HWL) to mechanical and thermal stimulation were measured. Rats were lightly anaesthetized with isoflurane and given an intraplantar injection of 50 µl of a suspension of heat-killed Mycobacterium butyricum (10 mg/ml) close to the right ankle joint. A contralateral injection of either saline or 0.3 mg U-50,488H was given twice intraplantarly per week (days 0, 4, 7, 11, 14 and 17). In order to investigate the involvement of peripheral opioid receptors, 0.3 mg of U-50,488H was co-injected into the contralateral paw with an equimolar dose of the peripherally acting opioid receptor antagonist naloxone methiodide. Non-arthritic control rats were injected with paraffin oil in the right hindpaw and were treated with saline injections contralaterally. All injections into the left hindpaw were given in a total volume of 100 µl.

All assessments and contralateral treatments were performed by the same investigator and at the same time of day. Body weight, hindpaw volumes and HWLs were monitored daily, and diameter of the ankle was measured on days before the injection into the contralateral hindpaw (days 0, 4, 7, 11, 14 and 21).

Experimental procedure for behavioural tests and signs of inflammation
Rats were trained with the experimental equipment as described above, using the Randall Selitto test and the hotplate test for half of the duration of each session. The order of measurements for the right and left hindpaw was continually alternated and the interval between measurements was approximately 5–7 min. The volume of each hindpaw and ankle joint diameter was measured following nociceptive tests. Two measurements were carried out for each test and the average value was used to quantify the percentage changes compared with pretreatment values for statistical analysis.

The Randall Selitto test (Type 7200; Ugo Basile, Comerio Va, Italy) was used to assess withdrawal thresholds to mechanical stimulation. A wedge-shaped, blunt piston with an area of 1x10 mm2 with a loading rate of 48 g/s was applied to the dorsal surface of the manually held hindpaw and the time required to initiate the withdrawal latency was measured in seconds. A cut-off time of 15 s was applied. Basal values of mechanical stimulation were 4.9 ± 0.2 s and 4.7 ± 0.2 s (right and left hindpaw, respectively, with no difference between the right and left side).

The withdrawal response to noxious heat was determined using the hotplate test. The entire ventral surface of the rat's hindpaw was placed on a hotplate which was maintained at a temperature of 50°C. The hindpaw withdrawal latency was measured in seconds and subsequently referred to as the HWL to thermal stimulation. The cut-off time was 50 s. Basal values of thermal stimulation were 6.8 ± 0.7 and 6.5 ± 0.6 s (right and left hindpaw, respectively, with no difference between the right and left sides).

The hindpaw volume was measured using a plethysmometer (Type 7150; Ugo Basile) and expressed in ml. The basal value of hindpaw volume was 1.0 ± 0.0 ml, with no difference between the right and left sides. The diameter of the ankles was measured using a calliper and is expressed in mm. Basal values of ankle joints were 5.8 ± 0.0 mm and 5.9 ± 0.0 mm (right and left ankle, respectively, with no difference between the right and left sides).

Severity scores for inflammation of the unilateral and contralateral hindpaws were evaluated by an independent observer as follows: 0 = no signs of inflammation; 1 = mildly inflamed; 2 = moderately inflamed; and 3 = severely inflamed. The systemic dissemination of arthritis, in terms of inflammation at other sites of the body beside the hindpaws, was assessed as absence (0) or presence (1).

COMP analysis
Blood samples were collected from untreated and treated rats on day 21 after inoculation. The blood was centrifuged at 1000 g for 10 min and the serum was stored at –70°C until analysis. Serum levels of cartilage oligomeric matrix protein (COMP) were measured by enzyme-linked immunosorbent assay using conditions similar to those described for the assay for human COMP [7]. The assay was modified by using rat COMP for coating of microtitre plates and for the standard curve included in each plate, and by using a polyclonal antiserum raised against rat COMP as the capture antibody [8].

Statistical analysis
Statistical analysis was carried out using SPSS software (Statistical Product and Service Solutions, release 12 Chicago, IL, USA). All data are expressed as the mean ± S.E.M. Each experimental group included 8–11 rats. A P value <0.05 was considered statistically significant.

For the treatment effect, each rat served as its own control. All changes in weight gain, hindpaw volume, ankle joint diameter and HWL are presented as percentage changes from the pretreatment value obtained on day 0, which was calculated according to the formula:

Formula

where P is the parameter measurement, x is the time after drug injection and 0 (zero) is the time before the first injection.

The t-test for independent samples was used to compare the percentage changes in weight gain, oedema formation, ankle joint volume, HWL to mechanical and thermal stimulation and the absolute values of serum COMP concentrations between the groups. The severity score of each hindpaw on day 21 was compared between the different groups by using the non-parametric Mann–Whitney U-test. The non-parametric {chi}2 test was used to identify the presence or absence of the systemic (non-contralateral) dissemination of the disease within the groups on day 21.

Chemicals
U-50,488H and naloxone methiodide were purchased from Research Biochemicals (Sigma, St. Louis, MO, USA) and dissolved in sterile 0.9% saline. Mycobacterium butyricum was obtained from Prof. S. Svensson (Uppsala University, Sweden).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Body weight
Injection of 50 µl of heat-killed Mycobacterium butyricum into the right hindpaw of the rat resulted in acute unilateral inflammation during the first 2 weeks and chronic polyarthritis within 21 days, with bilateral paw oedema. A significant decrease in body weight was measured in arthritic saline-treated rats compared with control non-arthritic animals during the acute (days 3 and 4) and chronic period (days 17–21) (P<0.05–0.001, t-test for independent samples, n = 10–11, data not shown). Compared with their original weight, arthritic saline-treated rats lost approximately 1.5% of their weight, whereas saline treated non-arthritic rats gained approximately 6%. No difference in weight gain was found between arthritic animals treated with saline and U-50,488H.

Hindpaw oedema
After intraplantar inoculation with Mycobacterium butyricum, the volume of the right hindpaw increased continuously during the entire period of 21 days (Fig. 1A), whereas the volume of the contralateral hindpaw was increased during days 3, 4, 11 and 13–21 (Fig. 1B) when compared with control non-arthritic rats. Contralateral administration of 0.3 mg U-50,488H decreased the volume of the right hindpaw on days 3, 4, 6, 8, 9 and 11–21 (Fig. 1A) and of the left hindpaw on days 1, 8, 11, 15, 17 and 19–21 (Fig. 1B) compared with the saline treatment in arthritic animals. The reduction in hindpaw oedema after treatment with U-50,488H was reversed by concomitant administration of the {kappa}-opioid agonist and naloxone methiodide on days 13–21 (right side) and 1, 5 and 15–21 (left side) (Fig. 1C and D).


Figure 1
View larger version (28K):
[in this window]
[in a new window]
  		FIG. 1. Changes in right (A) and left (B) hindpaw volume after contralateral treatment of arthritic rats with U-50,488H. Effect of naloxone methiodide on the right (C) and left (D) hindpaw volume after contralateral treatment of arthritic rats with U-50,488H. Data (mean ± S.E.M.) are expressed as percentage changes from day 0 (before induction of arthritis). *P<0.05, **P<0.01, ***P<0.001, significant differences between non-arthritic and arthritic control groups (n = 10–11); +P<0.05, ++P<0.01, significant differences between arthritic rats treated with saline or U-50,488H (n = 9–10); #P<0.05, ##P<0.01, ###P<0.001, significant differences between arthritic rats treated with U-50,488H or U-50,488H plus naloxone methiodide (NalMeth) (n = 8–9).

 
Diameter of ankle joints
In arthritic saline-treated rats, the diameter of the right ankle joint was increased during the entire period of 21 days (Fig. 2A), while the diameter of the left ankle joint was increased on days 17 and 21 when compared with non-arthritic animals (Fig. 2B). Administration of 0.3 mg U-50,488H into the contralateral hindpaw significantly reduced the diameter of the right and left ankles during days 7–21 and 17–21, respectively (Fig. 2A and B), compared with saline-treated arthritic rats. This effect was abolished by contralateral co-injection of 0.3 mg U-50,488H with an equimolar dose of naloxone methiodide (Fig 2C and D).


Figure 2
View larger version (22K):
[in this window]
[in a new window]
  		FIG. 2. Changes in diameter of right (A) and left (B) ankles after contralateral treatment of arthritic rats with U-50,488H. Effect of naloxone methiodide on the diameter of the right (C) and left (D) ankles after contralateral treatment of arthritic rats with U-50,488H. Data (mean ± S.E.M.) are expressed as percentage changes from day 0 (before induction of arthritis). **P<0.01, ***P<0.001 significant differences between non-arthritic and arthritic control groups (n = 10–11); +P<0.05, ++P<0.01, +++P<0.001, significant differences between arthritic rats treated with saline or U-50,488H (n = 9–10); #P<0.05, ##P<0.01, ###P<0.001, significant differences between arthritic rats treated with U-50,488H or U-50,488H plus naloxone methiodide (NalMeth) (n = 8–9).

 
Nociception
As shown in Fig. 3, injection of a pro-inflammatory agent decreased the HWL to mechanical stimulation bilaterally during the entire period of 21 days, except at days 5 (P<0.052) and 4 (P<0.057) in the right and left hindpaws, respectively, compared with control non-arthritic rats. Contralateral administration of 0.3 mg U-50,488H elevated HWL to mechanical stimulation on the right side on days 1–4, 7, 8, 10 and 15–21 (Fig. 3A) and on the left side during the entire period measured, except days 12 and 13 (Fig. 3B), when compared with saline-treated arthritic animals. Concomitant administration of U-50,488H and naloxone methiodide significantly reduced right and left hindpaw withdrawal latencies to noxious pressure compared with U-50,488H alone (Fig. 3C and D).


Figure 3
View larger version (37K):
[in this window]
[in a new window]
  		FIG. 3. Changes in right (A) and left (B) hindpaw withdrawal latency (HWL) to mechanical stimulation after contralateral treatment of arthritic rats with U-50,488H. Effect of naloxone methiodide on the right (C) and left (D) HWL after contralateral treatment of arthritic rats with U-50,488H. Data (mean ± S.E.M.) are expressed as percentage changes from day 0 (before induction of arthritis). *P<0.05, **P<0.01, ***P<0.001, significant differences between non-arthritic and arthritic control groups (n = 10–11); +P<0.05, ++P<0.01, +++P<0.001, significant differences between arthritic rats treated with saline or U-50,488H (n = 9–10); #P<0.05, ##P<0.01, ###P<0.001, significant differences between arthritic rats treated with U-50,488H or U-50,488H plus naloxone methiodide (NalMeth) (n = 8–9).

 
Nociceptive thresholds to thermal stimulation were also decreased as a result of inflammation on the right side during the entire period of 21 days, except at days 1, 3 and 5–7, compared with non-arthritic rats (P<0.05–0.001, t-test for independent samples, n = 10–11, data not shown). Left HWLs to heat stimulus were reduced in arthritic saline-treated animals, except for the first day after injection (P<0.05–0.001, t-test for independent samples, n = 10–11, data not shown). Contralateral administration of 0.3 mg U-50,488H did not affect the right HWL, except for an increase on days 16 and 20 (P<0.05, t-test for independent samples, n = 9–10, data not shown). However, HWL to thermal stimulation on the left side was significantly increased during days 2, 3, 5, 6, 8, 9, 13 and 16–19 compared with arthritic animals receiving saline injection (P<0.05–0.01, t-test for independent samples, n = 9–10, data not shown). Concomitant co-injection of U-50,488H with an equimolar dose of naloxone methiodide decreased HWL to thermal stimulation on the right side on days 16, 17 and 19 (P<0.05, t-test for independent samples, n = 8–9, data not shown) and on the left side on days 5, 8–13 and 15–17 compared with U-50,488H administration alone (P<0.05–0.01, t-test for independent samples, n = 8–9, data not shown).

Arthritic score
Results of arthritic score of the hindpaws are presented in Table 1. Control animals injected with paraffin in the right hindpaw and with saline in the contralateral hindpaw did not show any clinical signs of inflammation in the hindpaws or in other parts of the body at day 21. The severity score in arthritic saline-treated rats was significantly elevated both in the right and left hindpaw compared with non-arthritic rats (Table 1). In addition to the significant extension of inflammation to the contralateral hindpaw, a notable spread of inflammatory signs in the arthritic rats was also detected in other parts of the body, i.e. tail and/or forepaws, in 9 out of 10 arthritic rats (P<0.05, {chi}2 test, comparison within the group, results not presented).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Effect of contralateral treatment with 0.3 mg U-50,488H on the arthritic clinical score in rats

 
Administration of 0.3 mg U-50,488H into the contralateral hindpaw reduced the severity of arthritic scores for the right and left hindpaws on day 21 (Table 1). The effect was abolished by concomitant administration of U-50,488H with an equimolar dose of naloxone methiodide (Table 1).

In U-50,488H-treated animals, there was no significant spread of the inflammatory process into the contralateral hindpaw. In addition, the systemic dissemination of arthritis into other parts of the body was only notable in three out of nine rats (P>0.05, {chi}2 test, comparison within the group, results not presented). In contrast, all arthritic animals treated with U-50,488H together with naloxone methiodide developed signs of systemic dissemination of the disease (P<0.05, {chi}2 test, comparison within the group, results not presented).

COMP levels
Levels of COMP, a marker of cartilage turnover, in the serum of normal and arthritic saline- and U-50,488H-treated rats are shown in Table 2. On day 21 after inoculation, the serum COMP levels were significantly elevated by 255% in arthritic rats treated with saline compared with non-arthritic controls. Contralateral treatment with 0.3 mg U-50,488H significantly attenuated the increase in COMP caused by arthritis. In animals that received contralateral co-injection of U-50,488H and naloxone methiodide, COMP levels were similar to those measured in arthritic rats treated with saline.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Effect of contralateral treatment with 0.3 mg U-50,488H on serum levels of COMP in arthritic rats

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results reported in the present study indicate that repeated contralateral administration of a low dose (0.3 mg) of the {kappa}-opioid receptor agonist U-50,488H attenuated the development of chronic systemic inflammation in rats. Anti-inflammatory effects were obtained in the ipsilateral and contralateral hindpaws as well as other sites of the body after drug treatment. The mechanism of such anti-inflammatory effects might involve inhibition of nerve fibres on the contralateral side which normally respond to noxious mechanical stimuli. Indeed, HWLs to mechanical stimulation were prolonged on both ipsilateral and contralateral sides, whereas HWLs to thermal stimulation were enhanced mainly on the contralateral U-50,488H-treated side. A similar increase in HWLs to mechanical but not to thermal stimulation has previously been observed following contralateral U-50,488H administration in rats with acute carrageenan-induced inflammation [4] and mononeuropathy [5]. It is known that thin myelinated A{delta}-fibres mediate the transmission of mechanical stimuli, while unmyelinated C-fibres are involved in heat sensation [9]. The difference in the effects observed with U-50,488H on HWLs suggests that activation of {kappa}-opioid receptors situated on contralateral A{delta}-fibres plays an important role in antinociceptive pathways of the spinal cord, resulting in bilateral anti-inflammatory and antinociceptive effects. Furthermore, contralateral administration of U-50,488H into rats with adjuvant-induced arthritis also reduced levels of COMP on day 21, which indicates a chondroprotective effect. Changes in serum levels of COMP have previously been shown to reflect processes in cartilage in several experimental arthritis models. Thus, serum COMP concentrations correlate to cartilage damage as determined histologically in studies of glucocorticoid treatment or treatment with cytokine inhibitors in experimental arthritis [10, 11]. Importantly, changes in serum COMP do not correlate to changes in inflammatory variables in arthritis, and the pattern of COMP changes during the development of arthritis differs from the pattern of markers reflecting inflammation, i.e. hyaluronan and orosomucoid [12].

In the past decade, the existence of opioid receptors outside the central nervous system and the generation of analgesia by these peripheral receptors present on peripheral sensory nerves have been demonstrated [13]. Such analgesic effects are particularly prominent in painful inflammatory conditions, and have been demonstrated in both animals and humans. All three types of opioid receptors (µ, {delta} and {kappa}) appear to mediate peripheral opioid antinociception [14, 15]. A recent study in acute carrageenan-induced inflammation indicated that repeated local application of morphine in the inflamed hindpaw of the rat results in the development of tolerance [16]. In contrast, our present results suggest that repeated administration of the {kappa}-opioid agonist U-50,488H did not induce tolerance when administered during the acute and/or chronic stage of inflammation.

There is considerable evidence that the functional activity of the central and peripheral endogenous opioid system is enhanced by the acute and chronic imposition of noxious stimuli [17–20]. In the spinal cord, it has been demonstrated that the prodynorphin system is affected by acute noxious stimuli, such as ipsilateral hindpaw inflammation induced by carrageenan, formalin and Freund's adjuvant [17, 19]. Chronic exposure also has a long-term, sustained influence upon particular opioid networks [18, 20, 21]. Such stimuli profoundly enhance prodynorphin biosynthesis in spinal opioidergic neurons and stimulate the release of dynorphin peptides into the periphery at the site of tissue damage, where they act to reduce pain and inflammation [18, 22]. While a marked increase in levels of dynorphin B has been shown in the lumbar spinal cord of rats with chronic arthritis, no significant change or a reduction in the number of spinal {kappa}-opioid receptors was reported [20]. In the present study, U-50,488H was demonstrated to act through peripheral {kappa}-opioid receptors, which mediate its anti-inflammatory effects. Thus, it might be suggested that a lack of activation of the peripheral {kappa}-opioid receptors can be important in the generalization of a chronic inflammatory disease. This idea is supported by the findings of Wilson and colleagues [23] showing that the anti-arthritic effect of systemically administered U-50,488H might be mediated through ipsilateral activation of {kappa}-opioid receptors by the opioid agonist. Anti-inflammatory effects of U-50,488H were reported to be dose-dependent, while anti-arthritic effects were time-dependent with respect to the onset of disease.

Which are the mechanisms responsible for the anti-inflammatory and antinociceptive effects of contralateral U-50,488H during ipsilaterally induced arthritis? Our report and other studies indicate that during unilateral inflammatory processes there is a bilateral response of the nervous system. This is characterized by increased nerve activity [24, 25], exaggerated release of neuropeptides [26–28], hyperalgesia [3, 29, 30], plasma extravasation [31] and cartilage damage [32–34]. A tendency to a bilateral decrease in the number of {kappa}-opioid receptors in the dorsal root ganglia following acute unilateral hindpaw inflammation as well as the transport of these receptors in both antero- and retrograde directions as soon as 2 h after sciatic nerve ligation has been reported [35].

The antinociceptive action after contralateral administration of U-50,488H could be due to inhibition of nociceptive neurons in the spinal dorsal horn. This inhibition from the contralateral side might involve the same pathways as the ipsilateral side, e.g. presynaptic inhibition of calcium-dependent components of the action potential [36] and reduced release of excitatory pro-inflammatory compounds from peripheral sensory nerve endings [37]. All these mechanisms may account for the anti-inflammatory and analgesic actions of U-50,488H after contralateral administration in arthritic rats. Moreover, contralateral treatment might modulate or interact with spinal nociceptive transmission, since crossed transmission of spinal nociceptive signals between inflamed and non-inflamed sides has been demonstrated during the acute and chronic stages of monoarthritis [38]. This crossed transmission of nociceptive neuronal signals was affected by input from supraspinal descending inhibitory pathways.

It is well known that the immune system communicates with the peripheral nerve fibres through the release of neuropeptides and inflammatory mediators [22, 39–41]. Recently, Milligan et al. reported that spinal glia [42] and immune system mediators such as pro-inflammatory cytokines, reactive oxygen and complement mediate mirror-image in inflammatory neuropathic pain conditions. Chronic polyarthritis is considered to involve an inflammatory neuropathic pain component due to damage of nerve fibres following destruction [43] and abundant release of pro-inflammatory mediators due to activation of the immune system [44]. Ipsilateral local injection of selective inhibitors/antagonists prevents the development of bilateral nociception during inflammatory mononeuropathy [45]. In the present study, activation of {kappa}-opioid receptors following contralateral treatment might result in less input from the nervous system to the immune system on both the ipsilateral and contralateral sides, thereby affecting the sensitization and autoimmunization processes.

In conclusion, the results of the present study indicate that repeated contralateral treatment with a low dose of the {kappa}-opioid agonist U-50,488H decreased chronic inflammation in both the ipsilateral and contralateral hindpaws of the rat, as well as the spread of the disease to other sites of the body. Repeated contralateral administration of U-50,488H also produced an antinociceptive effect with respect to mechanical noxious stimulation; however, the effect was less pronounced than its anti-inflammatory effect. These effects were mediated through peripheral opioid receptors, since they were abolished by concomitant administration of naloxone methiodide. The present study shows the significant role of the contralateral side in the development of symmetrical responses and the dissemination of autoimmune inflammation.
Figure 4


   Acknowledgments
 
This study was supported by grants from the Lars Hiertas Memorial Foundation, the Karolinska Institutet Foundation and the Swedish Research Council. We acknowledge the technical assistance of Mette Lindell. M.S. was supported by fellowships from the Swedish Institute and Wenner-Gren Foundation.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Levine JD, Collier DH, Basbaum AI, Moskowitz MA, Helms CA. Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis. J Rheumatol 1985;12:406–11.[ISI][Medline]
  2. Kidd BL, Gibson SJ, O’Higgins F et al. A neurogenic mechanism for symmetrical arthritis. Lancet 1989;11:1128–30.
  3. Bileviciute-Ljungar I, Lundeberg T. Contralateral but not systemic administration of bupivacaine reduces acute inflammation in the rat hindpaw. Somatosens Motor Res 2000;17:285–93.[CrossRef][ISI][Medline]
  4. Bileviciute-Ljungar I, Spetea M. Contralateral but not systemic administration of the kappa-opioid agonist U-50,488H induces antinociception in acute hindpaw inflammation in rats. Br J Pharmacol 2001;132:252–8.[CrossRef][Medline]
  5. Bileviciute-Ljungar I, Spetea M. Contralateral, ipsilateral and bilateral treatments with kappa-opioid receptor agonist U-50,488H in mononeuropathic rats. Eur J Pharmacol 2004;494:139–46.[Medline]
  6. Bileviciute-Ljungar I, Lundeberg T. Contralateral treatment with xylocaine reduces nociceptive behaviour in mononeuropathic rats. Neuroreport 2000;11:291–5.[ISI][Medline]
  7. Saxne T, Heinegård D. Cartilage oligomeric matrix protein. A novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 1992;31:583–91.[Abstract/Free Full Text]
  8. Vingsbo-Lundgren C, Saxne T, Olsson H, Holmdahl R. Increased serum levels of cartilage oligomeric matrix protein in chronic erosive arthritis in rats. Arthritis Rheum 1998;41:544–50.[CrossRef][Medline]
  9. Jessell TM, Kelly DD. Pain and analgesia. In: Kandell ER, Schwartz JM, Jessell TM, eds. Principles of Neural Science. New York: Elsevier Science, 1991:385–99.
  10. Joosten LA, Helsen MA, Saxne T, van De Loo FAJ, Heinegård D, van den Berg WB. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 1999;163:5049–55.[Abstract/Free Full Text]
  11. Larsson E, Harris HE, Larsson A, Månsson B, Saxne T, Klareskog L. Corticosteroid treatment of experimental arthritis retards cartilage destruction as determined by histology and serum COMP. Rheumatology 2004;43:428–34.[Abstract/Free Full Text]
  12. Larsson E, Erlandsson-Harris H, Lorentzen JC et al. Serum concentrations of COMP, fibrinogen and hyaluronan distinguish inflammation and tissue destruction in experimental arthritis in rats. Rheumatology 2002;41:996–1000.[Abstract/Free Full Text]
  13. Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med 2003;9:1003–8.[CrossRef][ISI][Medline]
  14. Stein C, Yassouridis A. Peripheral morphine analgesia. Pain 1997;71:119–21.[CrossRef][ISI][Medline]
  15. Stein C, Millan MJ, Shippenberg TS, Peter K, Hertz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989;248:1269–75.[Abstract/Free Full Text]
  16. Perrot S, Guilbaud G, Kayser V. Differential behavioural effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation. Anesthesiology 2001; 94:870–5.[CrossRef][Medline]
  17. Idarola MJ, Douglass J, Civelli O, Naranjo JR. Differential activation of spinal cord dynorphin and enkephalin neurones during hyperalgesia: evidence using cDNA hybridization. Brain Res 1988;455:205–12.[CrossRef][ISI][Medline]
  18. Millan MJ, Millan MH, Czlonkowski A et al. A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis. J Neurosci 1986;6:899–906.[Abstract]
  19. Millan MJ, Czlonkowski A, Morris B et al. Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat. Pain 1988;35:299–312.[CrossRef][Medline]
  20. Spetea M, Rydelius G, Nylander I et al. Alteration in endogenous opioid systems due to chronic inflammatory pain conditions. Eur J Pharmacol 2002;435:245–52.[CrossRef][ISI][Medline]
  21. Ballet S, Mauborgne A, Hamon M, Cesselin F, Collin E. Altered opioid-mediated control of the spinal release of dynorphin and met-enkephalin in polyarthritic rats. Synapse 2000;37:262–72.[CrossRef][Medline]
  22. Stein C, Hassan AHS, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA 1990;87:5935–39.[Abstract/Free Full Text]
  23. Wilson JL, Nayanar V, Walker JS. The site of anti-arthritic action of the kappa-opioid, U-50,488H, in adjuvant arthritis: importance of local administration. Br J Pharmacol 1996;118:1754–60.[ISI][Medline]
  24. Chahl LA, Ladd RJ. Local oedema and general excitation of cutaneous sensory receptors produced by electrical stimulation of the saphenous nerve in the rat. Pain 1976;2:25–34.[Medline]
  25. Rees H, Sluka KA, Lu Y, Westlund KN, Willis WD. Dorsal root reflexes in articular afferents occur bilaterally in a chronic model of arthritis in rats. J Neurophysiol 1996;76:4190–3.[Abstract/Free Full Text]
  26. Bileviciute I, Lundeberg T, Ekblom A, Theodorsson E. Bilateral changes of substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity in rat knee joint synovial fluid during acute monoarthritis. Neurosci Lett 1993;153:37–40.[CrossRef][ISI][Medline]
  27. Yu L-C, Hansson P, Brodda-Jansen G, Theodorsson E, Lundeberg T. Intrathecal CGRP8-37-induced bilateral increase in hindpaw withdrawal latency in rats with unilateral inflammation. Br J Pharmacol 1996;117:43–50.[Medline]
  28. Bileviciute I, Stenfors C, Theodorsson E, Lundeberg T. Unilateral injection of calcitonin-gene-related peptide (CGRP) induces bilateral oedema formation and release of CGRP-like immunoreactivity. Br J Pharmacol 1998;125:1304–12.[Medline]
  29. Kayser V, Guilbaud G. Local and remote modifications of nociceptive sensitivity during carrageenin-induced inflammation in the rat. Pain 1987;28:99–107.[CrossRef][ISI][Medline]
  30. Radhakrishnan R, Moore SA, Sluka KA. Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain 2003;104:567–77.[CrossRef][ISI][Medline]
  31. Kidd BL, Cruwys SC, Garrett NE, Mapp PI, Jolliffe VA, Blake DR. Neurogenic influences on contralateral responses during experimental rat monoarthritis. Brain Res 1995;688:72–6.[Medline]
  32. Andersson SE, Lexmuller K, Ekstrom GM. Physiological characterisation of mBSA antigen induced arthritis in the rat. I: Vascular leakiness and pannus growth. J Rheumatol 1998;25:1772–7.[ISI][Medline]
  33. Decaris E, Guingamp C, Chat M et al. Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis Rheum 1999;42:1951–60.[CrossRef][ISI][Medline]
  34. Meyer P, Burkhardt H, Palombo-Kinne E et al. 123-I-antileukoproteinase scintigraphy reveals microscopic cartilage alterations in the contralateral knee joint of rats with "monoarticular" antigen-induced arthritis. Arthritis Rheum 2000;43:298–310.[Medline]
  35. Ji R-R, Zhang Q, Law P-Y, Low HH, Elde R, Hökfelt T. Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 1995;15:8156–66.[Abstract]
  36. Werz MA, Macdonald RL. Heterogenous sensitivity of cultured dorsal root ganglion neurones to opioid peptides selective for mu- and delta-opioid receptors. Nature 1982;299:730–3.[Medline]
  37. Yonehara N, Imai Y, Inoki R. Effects of opioids on the heat stimulus-evoked substance P release and thermal edema in the rat hindpaw. Eur J Pharmacol 1988;151:381–7.[CrossRef][ISI][Medline]
  38. Danziger N, Weil-Fugazza J, Le Bars D, Bouhassira D. Stage-dependent changes in the modulation of spinal nociceptive neuronal activity during the course of inflammation. Eur J Neurosci 2001;13:230–40.[ISI][Medline]
  39. Hua X-Y, Yaksh TL. Pharmacology of the effects of bradykinin, serotonin, and histamine on the release of calcitonin gene-related peptide from C-fiber terminals in the rat trachea. J Neurosci 1993;13:1947–53.[Abstract]
  40. Akoev GN, Filippova LV, Sherman NO. Mast cell mediators excite the afferents of cat small intestine. Neuroscience 1996;71:1163–6.[CrossRef][ISI][Medline]
  41. Bileviciute I, Lundeberg T, Ekblom A, Theodorsson E. The effect of a single dose of hrIL-1 alpha on substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity in cerebrospinal fluid, plasma and knee joint synovial fluid in rat knee. Regul Pept 1994;53:71–6.[Medline]
  42. Milligan ED, Twining C, Chacur M et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain. J Neurosci 2003;23:1026–40.[Abstract/Free Full Text]
  43. Calza L, Pozza M, Zanni M, Manzini CU, Manzini E, Hökfelt T. Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study. Neuroscience 1998;82:575–89.[CrossRef][ISI][Medline]
  44. Ulfgren AK, Grondal L, Lindblad S et al. Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implication for treatment. Ann Rheum Dis 2000;59:439–47.[Abstract/Free Full Text]
  45. Twining CM, Sloane EM, Milligan ED et al. Peri-sciatic proinflammatory cytokines, reactive oxygen species, and complement induce mirror-image neuropathic pain in rats. Pain 2004;110:299–309.[CrossRef][Medline]
Accepted 9 September 2005


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/3/295    most recent
kei156v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bileviciute-Ljungar, I.
Right arrow Articles by Spetea, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bileviciute-Ljungar, I.
Right arrow Articles by Spetea, M.
Related Collections
Right arrow Experimental Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?