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Anesth Analg 1999;89:409
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Intraarticular and Periarticular Opioid Binding in Inflamed Tissue in Experimental Canine Arthritis

Helen L. Keates, BVSc*, Tess Cramond, FRCA, FANZCA{dagger}, and Maree T. Smith, PhD{ddagger}

School of *Veterinary Science and Animal Production, and {dagger}Pharmacy, The University of Queensland, St Lucia; and {ddagger}Multidisciplinary Pain Centre, Royal Brisbane Hospital, Brisbane, Queensland, Australia

Address correspondence and reprint requests to Helen L. Keates, BVSc, School of Veterinary Science and Animal Production, The University of Queensland, St Lucia, Queensland, 4072, Australia. Address e-mail to h.keates{at}mailbox.uq.edu.au


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Small-dose (1 mg) intraarticular morphine has been used successfully in many studies to provide long-lasting analgesia after arthroscopic knee surgery. We used radioligand binding to determine whether these effects could be mediated by opioid binding sites in the joint, particularly after the induction of inflammation. Inflammation was induced by the injection of oleyl alcohol (20 µL) in sterile peanut oil (0.25 mL) into the left radiocarpal joint of 27 dogs, and the dogs were euthanized at 12 h. The articular and periarticular tissues from both treated and control joints were collected, and membranes were prepared for equilibrium binding assays. The density of specific opioid binding was markedly enhanced (P < 0.05) in homogenates prepared from the treated relative to those from the control joint. The binding affinities (KD values) for morphine and naloxone (mean ± SEM) were approximately one one-hundredth (79 ± 17 nM and 124 ± 5.5 nM, respectively) that of the corresponding published affinities in brain tissue. However, the binding site densities were approximately one hundred times larger (Bmax = 1032 ± 265 and 543 ± 51 fmol/mg of protein) than the respective published values in brain tissue. These findings imply that the opioid binding sites, found in the inflamed articular and periarticular tissues in this study, are similar to those of putative µ3-opioid binding sites that appear to be present on cultured thymocytes and in the airways of rats and humans.

Implications: The high density of opioid binding sites found in inflamed canine joint tissue supports the clinical use of intraarticular opioids in the treatment of postoperative and chronic inflammatory joint pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In 1991, Stein et al. (1) reported the successful use of small-dose (1 mg) intraarticular (IA) morphine for the relief of postoperative pain in patients after arthroscopic knee surgery. Since then, there have been numerous clinical reports regarding the efficacy of IA morphine for postoperative pain relief in humans after knee surgery (2), most of which have been positive. Additionally, a study in dogs (3) showed that effective analgesia was provided by IA morphine (0.1 mg/kg) after exploratory stifle (knee joint) arthrotomy and that the level of analgesia produced was comparable to that of epidural morphine (0.1 mg/kg) (3). In contrast, Sammarco et al. (4) reported that, although dogs experienced some analgesia after administration of IA morphine (0.1 mg/kg) after arthrotomy for cruciate ligament repair, the effect was less than that produced by 0.5% IA bupivacaine (0.5 mL/kg). However, because these dogs were premedicated with the opioid oxymorphone, the latter results may have been confounded by a synergistic interaction between the opioid (oxymorphone) and the local anesthetic (bupivacaine) as reported previously in rats (5).

Several studies show that opioids injected directly into the inflamed rat paw evoke pain relief in a dose-dependent, reversible, and stereo-specific manner (6–8). Additionally, autoradiographic studies show that ß-endorphin binds to both small-diameter nerves and to immune cells in inflamed tissue (9,10), with binding site density increasing as inflammation develops (9). However, attempts to demonstrate specific opioid binding using conventional radioligand binding techniques in synovial tissue homogenates have been less successful. In 1992, Lawrence et al. (11) reported specific [3H]-naloxone binding in only 6 of 11 samples of inflamed synovial tissue obtained from patients undergoing arthroscopic surgery. These results were characterized by low total binding of radioligand, with specific binding (mean ± SEM) representing only 18% (±4%) of total binding.

A number of models of arthritis have been characterized in terms of inflammatory changes. Polyarthritis has been induced in rats by injection of 0.1 mL of oleyl alcohol subcutaneously into the tail base (12). In this study, a novel model of acute monoarthritis induced by IA injection of oleyl alcohol was used to produce tissue for radioligand binding studies. Our model has been adapted from acute inflammatory models involving IA injection of oleyl alcohol in rats and rabbits (J. McNeil, University of Adelaide Department of Medicine, Modbury Public Hospital, Modbury, Australia, personal communication, 1966).

This study was designed to use radioligand binding techniques to characterize specific opioid binding in homogenates prepared from both inflamed and noninflamed articular and periarticular joint tissue in a canine model of acute experimental inflammation.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
[N-Methyl-3H]morphine, (84.5 Ci/mmol) and [N-Allyl-2,3-3H]naloxone (58.5 Ci/mmol) were purchased from DuPont/NEN (Boston, MA). [D-ala2,N-Me-Phe4,Gly5ol]- enkephalin (DAMGO), [D-Pen2,5]enkephalin (DPDPE), U69,593, naloxone HCl, and pethidine were obtained from Sigma (Poole, Dorset, UK). Cis-9-octadecen-1-ol (oleyl alcohol), TRIZMA base (Tris[hydroxymethyl]amino-methane), HEPES (N-(2-hydroxyethyl]piperazine-N-[2-ethane sulfonic acid]), and collagenase were purchased from Sigma Chemical Co. (Sydney, Australia). Morphine HCl and peanut oil were purchased from the Pharmacy Department, Royal Brisbane Hospital and Biotech International Ltd., respectively (Brisbane, Australia). EppendorfTM microfuge tubes (1.5 mL) and porcine pancreas elastase were purchased from Disposable Products (Brisbane, Australia) and Calbiochem (Sydney, Australia), respectively.

Ethical clearance was obtained from the Animal Experimentation Ethics Committee of The University of Queensland. Twenty-seven dogs (19 male and 8 female) of mixed breeds were housed in the School of Veterinary Science at The University of Queensland, in runs of 1 x 2 meters with water available ad libitum. Dogs were fed a commercial dry food diet once daily and had daily access to an exercise yard. Dog forelimbs were examined by palpation, flexion, and extension of the radiocarpal joints, and gait was observed and scored as described by McLaughlin et al. (13). Additional variables assessed included the relative warmth (to touch) of the left to right carpus, the left and right carpal joint circumferences, and the rectal temperature.

After premedication with acepromazine (0.1 mg/kg subcutaneously), anesthesia was induced with propofol and maintained with isoflurane delivered in oxygen. Aspirates of synovial fluid were obtained from each radiocarpal joint using a 26-gauge needle attached to a 1-mL syringe. After administration of oleyl alcohol (proinflammatory agent) 20 µL in sterile peanut oil 0.25 mL into the left "treated" joint, dogs were allowed to recover from anesthesia. Dogs were examined at 6 h and 12 h, and then euthanized with an overdose of pentobarbitone sodium. After collection of synovial fluid samples, the skin was removed from the surface of the joints, and the full thickness of tissue overlaying and forming the individual joint capsules was removed. A small sample of tissue was placed into formalin for histologic examination, and the remainder was placed into ice-cold sucrose solution (0.32 M) for use in subsequent radioligand binding studies. To optimize tissue integrity, the tissue was frozen at -20°C overnight and then stored at -70°C until required (14).

Total nucleated cells were counted in all synovial fluid samples, and differential nucleated cell counts were performed on "treated" and "control" samples from 12 dogs. Classification of inflammatory cells other than polymorphonucleocytes (PMN) in synovial fluid from treated joints was difficult because there were many cells in stages intermediate between recognizable lymphocytes, monocytes, and macrophages. Therefore, the term mononuclear cells has been used to describe inflammatory cells with a single nucleus.

Tissues collected from each joint were finely chopped before incubation (3 h at 37°C) with collagenase 1 mg/mL and elastase 15 U/mL in HEPES-Tris buffer (20 mM, pH 7.4, 4 mL/g wet weight original tissue). After homogenization (45 s), the digestion mixture was filtered through a nylon filter (600 µm) and centrifuged at 48,000g for 20 min at 4°C. The tissue pellet was resuspended (5 mL/g wet weight of original tissue) in ice cold HEPES-Tris buffer (20 mM, pH 7.4) and refiltered. The membrane preparation was frozen at -20°C for 16 h and then stored at -70°C until required. Preliminary studies showed that inclusion of additional wash steps or an incubation period (40 min) at 37°C resulted in loss of specific opioid binding, a finding similar to that reported by Cabot et al. (15) for opioid binding sites in slices of peripheral airway tissue. The final membrane preparation was also difficult to handle because agitation resulted in clump formation.

Radioligand binding assays were performed in EppendorfTM tubes using 50 µL of membrane suspension (approximately 860 µg of protein) in a total volume of 0.5 mL. Protein concentrations were determined by the method of Lowry et al. (16). Because preliminary studies indicated that the opioid binding sites were of relatively low affinity, centrifugation (21,000g, 4°C for 30 min) was used for assay termination. After centrifugation, the supernatant was removed by gentle suction, and the pellet was washed with ice-cold HEPES-Tris buffer (20 mM, pH 7.4). After draining overnight, the base of each tube containing the pellet was clipped into a scintillation vial (4 mL) to which 300 µL of water was added. After 24 h, scintillation fluid (4 mL) was added and the samples were counted in a Packard Tricarb 2700 Liquid Scintillation Counter (Packard Instrument Company, Meriden, CT).

The time to establish equilibrium binding was determined using [3H]-morphine. Nonspecific binding was quantified using unlabeled morphine in a concentration of 10 µM. Because the density of specific binding showed marked interindividual variability between dogs, the data are expressed as a percentage of specific binding achieved at 150 min. Assay incubations were performed in triplicate on three different tissues (representing three individual dogs) at 25°C for 2 h using [3H]-morphine 1.0 nM or [3H]-naloxone 1.0 nM. The concentration range of unlabeled opioids used in displacement assays was 1 nM–10 µM. The displacement of [3H]-morphine by the opioid peptides, DAMGO (µ-selective), DPDPE ({delta}-selective), and U69,593 ({kappa}-selective) in a single concentration of 10 µM was investigated. Additional displacement assays were performed using [3H]-morphine and unlabeled morphine in the presence and absence of DAMGO (10 µM).

Paired t-tests were used to determine 1) whether there were significant differences in pre- and posttreatment immune cell counts in the inflamed limb relative to the control limb and 2) whether sampling significantly altered cell counts in the control limb. The statistical significance criterion was P < 0.05. The values for binding affinity (KD), binding inhibition constant (Ki), and binding site density (BMAX) were estimated from displacement assay binding data using GraphPadTM Prism (GraphPad Software, San Diego, CA). Linear regression analysis was performed between binding site density data and mononuclear cell counts using GraphPadTM Instat.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
At 12 h posttreatment, the maximum score of 4 was observed for lameness in 13 dogs and for flexion in 10 of the 27 dogs investigated. There was no lameness in control limbs despite collection of similar numbers of joint fluid samples. In two dogs, the baseline flexion scores of the control joint were 1 and 0.5 but this was no longer detectable at 12 h. Changes in joint circumference (expressed as a percentage of pretreatment circumference) were significantly greater (P < 0.01) in the treated joint relative to the control joint at both 6 and 12 h after initiation of inflammation. In 26 of the 27 dogs, the skin over the treated carpus was palpably warmer than that of the control limb. At 12 h posttreatment, the mean ± SEM rectal temperature was 0.4 ± 0.1°C higher than at baseline. Behaviorally, 2 of the 27 experimental dogs were subdued at both 6 and 12 h, and a third was subdued at 12 h after the onset of joint inflammation. The other 24 dogs were active, alert, and responsive throughout the 12-h experimental period.

The immune cell response to IA oleyl alcohol in dogs has not been described previously. Specifically, baseline synovial fluid cell counts (mean ± SEM) did not differ significantly (P > 0.05) between treated joints (380 ± 52 x 106/L) and control joints (416 ± 76 x 106/L). However, by 12 h after initiation of inflammation, the mean ± SEM nucleated cell count had increased by approximately 100-fold (88,463 ± 10,554 x 106/L) in treated joints relative to control joints (759 ± 174 x 106/L) in a manner similar to that described after IA administration of Freund’s Complete Adjuvant or sodium urate crystals into canine knee joints (Table 1). No lymphocytes were observed in 17 of 24 baseline synovial fluid samples, and lymphocyte counts were low (range 24–67 x 106/L) in the other seven samples. There were no cells that could be clearly identified as lymphocytes in synovial fluid collected at 12 h from either control or treated joints.



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  		Table 1. Comparative Effect of Freund’s Complete Adjuvant, Sodium Urate Crystals, and Oleyl Alcohol on Synovial Fluid Immune Cell Counts

 
In inflamed joints, PMN numbers (mean ± SEM) in synovial fluid increased more than 3000-fold (from 25 ± 8 x 106/L to 85,649 ± 14,693 x 106/L), and mononuclear cell numbers increased 34-fold (from 357 ± 52 x 106/L to 9834 ± 1406 x106/L) relative to baseline, by 12 h posttreatment (Table 2). An 11-fold increase in the (mean ± SEM) number of PMN (49 ± 35 to 574 ± 274) was observed in synovial fluid from control joints at 12 h, but because of the large variance, this did not attain statistical significance (P > 0.05) relative to baseline levels (Table 2). Although histologic changes in sections of treated joint tissue varied between dogs, there was a consistent mild edema with intravascular and perivascular accumulation of inflammatory cells (both PMN and mononuclear cells) involving the small blood vessels.


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  		Table 2. The Effect of Oleyl Alcohol Administration (20 µl in 250 µl of Peanut Oil) on the Differential Immune Cell Count in Synovial Fluid of the Treatment (Left) Radiocarpal Joint and Control (Right) Radiocarpal Joint
 
Preliminary studies (data not shown) showed that [3H]-morphine binding was completely reversible by the nonselective opioid antagonist naloxone. Specific binding of radiolabeled morphine reached equilibrium by 90 min (Fig. 1). Hence, subsequent opioid binding assays were incubated with radioligand for 2 h. The mean ± SEM binding affinity (KD) for morphine was 79 ± 17 nM and the corresponding binding site density (Bmax) was 1032 ± 265 fmol/mg protein. The mean ± SEM KD and Ki values for displacement of [3H]-naloxone by naloxone and morphine, respectively, were 124 ± 6 nM and 145 ± 37 nM. The corresponding Bmax values were 542 ± 51 fmol/mg protein and 757 ± 153 fmol/mg protein, respectively (Table 3). The mean ± SEM increase in the density of specific opioid binding in inflamed relative to control joint tissue was 50-fold (range 2.2–488-fold), irrespective of whether specific binding was determined using [3H]morphine or [3H]naloxone. Importantly, there were no significant differences (P > 0.05) between the levels of nonspecific opioid binding found in treated versus control joint tissue. There was a high degree of correlation (r2 = 0.82) between the mononuclear cell count in the synovial fluid and the morphine binding site density in the inflamed tissue, although this did not reach statistical significance (P > 0.05) because of the small sample size (n = 3) for which paired data were available.



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  		Figure 1. Equilibrium binding assays (n = 4) performed for 150 min at 25°C in membranes prepared from inflamed canine radiocarpal joint tissues. Data represent the mean ± SEM specific binding at each time point expressed as a percentage of the specific binding at 150 min.

 

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  		Table 3. Displacement Assays for *M and *N by M and N, respectively
 
The µ-opioid peptide, DAMGO (10 µM) did not displace [3H]-morphine binding; rather, it appeared to enhance specific morphine binding in membranes prepared from both treated and control joint tissues. Further analysis revealed that the mean ± SEM KD for morphine in the presence of DAMGO (109 ± 23 nM) was not significantly different from that in its absence (79 ± 18 nM). However, in the presence of DAMGO, the density of morphine binding sites appeared to increase 7-fold to 7356 ± 870 fmol/mg protein (Fig. 2). DPDPE ({delta}-opioid peptide) and U69,593 ({kappa}-opioid peptide) neither displaced nor enhanced [3H]-morphine binding (Fig. 2).



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  		Figure 2. A, Displacement/enhancement of [3H]-morphine binding by the opioid peptide ligands DAMGO (µ-selective), DPDPE ({delta}-selective), and U69593 ({kappa}-selective) in a concentration of 10 µM where 100% represents specific morphine binding. Data are presented as mean ± SEM (n = 3). B, Displacement of [3H]-morphine by morphine in the presence (*M/M + DAMGO) and absence (*M/M) of 10-µM DAMGO. Data points represent mean ± SEM (n = 3).

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
By 12 h after initiation of inflammation in the left radiocarpal joint, there was a marked increase (approximately 50-fold) in the mean density of nonconventional opioid binding sites in inflamed articular and periarticular tissue (Table 2). Displacement assays revealed similar mean ± SEM equilibrium binding parameters (KD/Ki and Bmax values) for the displacement of [3H]-morphine by morphine (79 ± 17 nM), [3H]-naloxone by naloxone (124 ± 6 nM), and [3H]-naloxone by morphine (145 ± 37 nM). These binding affinities for morphine and naloxone were approximately two orders of magnitude lower and the corresponding binding site densities were approximately 100-fold higher than those reported for conventional opioid binding sites in brain tissue (20). Additionally, the nonconventional nature of these opioid binding sites was reinforced by the observation that they were opioid alkaloid sensitive and opioid peptide insensitive, in a manner similar to opioid binding sites in airway homogenate (21,23) and on cultured thymocytes (22). Intriguingly, DAMGO (10 µM) appeared to increase the density of specific morphine binding seven-fold in canine joint tissue homogenate without a change in binding affinity. However, it is also possible that DAMGO may have displaced an endogenous substance that had not been removed during tissue processing, caused by the truncation of the usual wash and incubation steps. Clearly, this requires further investigation.

It is clear that opioid binding sites in inflamed canine joint tissue have characteristics similar to those of putative µ3-opioid receptors reported previously 1) on cultured thymocytes after (but not before) stimulation with the proinflammatory cytokine, interleukin-1 (22) and 2) in the airways of rats and humans (21,23). It is therefore conceivable that the putative µ3-opioid receptors found previously in rat and human airways (21,23) may have been located on activated immune cells within the airways because lung tissue is well endowed with immune cells that are under constant antigenic stimulation.

Importantly, in the current study, noninflamed canine joint tissue was shown to contain minimal specific opioid binding. In contrast, a high density of specific, putative µ3-opioid binding sites was evident by 12 hours in the inflamed joint, suggesting that the large increase in specific opioid binding observed may have been associated with the migration of activated immune cells into the joint, in a manner similar to that reported in the inflamed rat paw (24). In support of this proposal, canine joint tissue that showed significant levels of specific opioid binding, also had markedly elevated levels (100-fold) of nucleated cells in the associated synovial fluid relative to control joints (Table 2). This increase was predominantly a result of an increase in PMN (150-fold), but there was also a 40-fold increase in the number of mononuclear cells. Because of the activity-related changes in the cells examined, it was difficult to define the origin of the mononuclear cells. Because both exudate and immune cells from blood may enter inflamed tissue and the joint space, it is likely that the quantitative changes found in the immune cell content of synovial fluid reflect the changes in the neighboring tissues. Interestingly, the number of mononuclear cells in synovial fluid appeared to be correlated (r2 = 0.82) with the opioid binding site density in the corresponding tissue sample for the three dogs for which these data were available. Further work with greater numbers of samples is needed to confirm this relationship. Taken together, these data suggest that the opioid binding sites identified in the inflamed joint tissue homogenate preparation are putative µ3-opioid receptors located on mononuclear immune cells that migrated into the tissue in response to the release of inflammatory mediators. This proposed mechanism is similar to that reported by Cabot et al. (24) in the inflamed rat paw.

Two of the 27 dogs, in this study, had mild withdrawal responses on flexion of both radiocarpal joints before the induction of lameness (scores in range, 0.5–1). However, because this was no longer evident in control joints by 12 h posttreatment, it may have been because the dogs were more focused on the inflamed joints. Another possibility is that endogenous opioids were released into the joint from activated immune cells in a manner analogous to that reported for rats with experimentally induced peripheral inflammation (24). Because the synovial membrane is rich in sensory nerve endings (25), it is also possible that an increase in axonal transport of opioid binding sites from the spinal cord to nerve terminals in inflamed joint tissue occurred in response to the inflammatory insult. However, as studies in rats showed that this mechanism was not significant until three days after the induction of inflammation (9), it is unlikely to have accounted for the increase in opioid binding sites found just 12 h after initiation of inflammation in canine radiocarpal joints.

Although the protein concentration used in the binding studies described herein was approximately twice that used in previous studies in airway homogenate (23), lower levels of specific binding were obtained. It is probable that significant amounts of protein from fibrous tissue (collagen and elastin) were present in joint tissue homogenates, which is supported by the observation that agitation of the homogenized joint tissue resulted in clump formation.

In summary, by 12 hours after initiation of inflammation in the left radiocarpal joint of dogs, there was a marked increase (100-fold) in the immune cell concentration in synovial fluid that was accompanied by a 50-fold increase in the density of specific [3H]-morphine binding in the articular and periarticular tissue. Because the morphine binding characteristics in this tissue were similar to those of putative µ3-opioid binding sites reportedly found on immune cells (22) and in the airways of rats and humans (21,23), the results of this study imply that the high density of opioid binding sites found in the inflamed canine joint are present on activated immune cells that infiltrated the joint tissue after the onset of inflammation.


   Acknowledgments
 
This research was supported financially by the John and Mary Kibble Bequest Fund and The University of Queensland Research Grants Scheme.


   Footnotes
 
HLK was supported by an Australian Postgraduate Award.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 16, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press