Multimodal pain control has been used in the management of surgical and chronic pain syndromes.1–3 Several approaches to multimodal pain control have been proposed, including attempts to determine and suppress the inflammatory cascade of the pain profile, suppress afferent pain pathways, and inhibit neuronal transmission.4 Neuronal transmission of nociceptive stimuli has been the focus of several recent studies. Classes of drugs evaluated for potential benefit as centrally acting analgesics include opioids, norepinephrine and serotonin reuptake inhibitors,5 neurokinin-1 receptor antagonists,6,7 vanilloid receptor antagonists,8,9 COX inhibitors acting on constitutive spinal COX,1,10 NMDA receptor antagonists,2,11–17 and PLA2 inhibitors.18,19
Several NMDA receptor antagonists have been evaluated for their role in pain control.3,11,12 The NMDA receptor comprises 3 known subtypes (subunits): NR1, NR2 (A, B, C, and D), and NR3 (A and B).3,20 The NR2A- and NR2B-containing receptors have been associated with high-conductance postsynaptic depolarization, and NR2B has been more specifically associated with fewer psychomimetic effects.20 Although many NMDA receptor antagonists selective for the NR2B subunit have been developed, perzinfotel (which has a high affinity and selectivity for the glutamate site on the NR2A subunit) has shown promise in an early study11 in which rats had decreased hypersensitivity and decreased allodynia along with no extrapyramidal signs. Gene expression of both NR2A and NR2B mRNA have been upregulated after inflammation, which supports their role in central sensitization.14 Studies in dogs have revealed that perzinfotel lowers the minimum alveolar concentration of isoflurane in a dose-dependent manner2 and that a combination of perzinfotel with fentanyl results in a lower minimum alveolar concentration of isoflurane than does either drug alone.15
Phospholipase A2 is an enzyme superfamily containing 15 identified groups21 that is known to act on phospholipid membranes to release fatty acid chains that lead to the formation of arachidonic acid22 and subsequent eicosanoids involved in corporeal homeostasis and the inflammatory state.23 It is also known that generation of arachidonic acid substrate by PLA2 is the rate-limiting step of eicosanoid formation24 and has been a target for development of pharmaceuticals that can inhibit this step, with the eventual goal of providing analgesia through modulation of the inflammatory process. In addition to modulation of inflammation, PLA2 has a cytosolic presynaptic role in the transmission of nociceptive stimuli.25
The purpose of the study reported here was to examine the ability of preemptive treatment with perzinfotel (an NMDA receptor antagonist) and a proprietary PLA2 inhibitor to attenuate lameness in dogs with sodium urate–induced synovitis. The effectiveness of perzinfotel and the PLA2 inhibitor was evaluated by use of clinical and GRF assessments of lameness.
Materials and Methods
Animals—Eight adult purpose-bred mixed-breed dogs (4 males and 4 females) of typical body condition were used in the study. Physical and orthopedic examinations were performed on each dog. In addition, screening radiographs were obtained of both of the hip, stifle, and elbow joints of each dog. Dogs were excluded from the study when there was evidence of any lameness or health concerns. Dogs received routine vaccinations and anthelmintics. All dogs were housed in a climate-controlled animal housing facility at the University of Georgia; they were fed a commercially available maintenance diet and were offered water ad libitum. The study was approved by the University of Georgia Institutional Animal Care and Use Committee.
Study design—A blinded 4-way crossover study was performed. Dogs were assigned by use of a randomization procedure (randomization table created by use of a web-based programa) to receive treatments, which included perzinfotel (10 mg/kg, IM), a proprietary PLA2 inhibitorb (10 mg/kg, PO), carprofen (4.4 mg/kg, SC; positive control treatment), and no treatment (negative control treatment). Treatments were given once daily for 4 days. Any adverse event (eg, ocular discharge, nasal discharge, coughing, emesis, diarrhea, sedation, signs of depression, recumbency, reluctance to move, ataxia, salivation, rapid or labored breathing, muscle tremors, or convulsions) was recorded. Synovitis was induced on the fourth day of treatment via intra-articular injection of 1.0 mL of a solution of sodium urate (5.0 mg/mL) prepared as described elsewhere.12 Injections were administered alternately in the left or right stifle joint of each dog (left stifle joint for period 1, right stifle joint for period 2, left stifle joint for period 3, and right stifle joint for period 4) 1 hour before administration of the last treatment dose. A single observer (BTT) who was not aware of the treatment administered to each dog measured GRF and performed a clinical lameness evaluation before sodium urate injection (baseline [time 0]) and at 2, 4, 6, 8, 12, and 25 hours after sodium urate injection.
A washout period of 21 days was allowed between subsequent treatment periods (21 days between sodium urate injections, with treatments starting 3 days before the sodium urate injections). Each dog received all 4 treatments (8 dogs/treatment).
Dogs were evaluated every 2 hours for the first 8 hours after sodium urate was injected and then at 12 and 24 hours. If any dog had a cumulative subjective lameness score ≥ 11 or had signs of pain that included vocalization or dramatic changes in behavior after sodium urate injection, it was deemed to be in excessive pain and immediately withdrawn from the study; such dogs were then to be administered an NSAID or opioid as necessary to control signs of pain.
Data collection—Clinical lameness scoring was performed and recorded for each dog at each time point by use of a subjective lameness scoring system described elsewhere (Appendix).26 The GRF data were collected by use of 2 force platesc mounted in series, a computer, and software.d From the GRF data, PVF, VI, PCBF, CBI, PCPF, and CPI were determined. All trials were performed at a trotting speed of 1.70 to 2.10 m/s and an acceleration and deceleration of 0.50 m/s/s by 1 of 2 experienced handlers (LRR and SA). Each dog was led across the force plates by the same handler within each period of the experiment. Trials were only accepted when there was a single hind limb footfall on each force plate and a standard trotting gait was maintained with no extraneous movements. At each time point for each dog, 6 observations were recorded for both hind limbs (healthy and sodium urate—injected stifle joints).
Statistical analysis—Repeated-measures ANOVAs were used to evaluate the effects of treatment (perzinfotel, PLA2 inhibitor, positive control treatment, and negative control treatment) on PVF, VI, PCBF, CBI, PCPF, CPI, and subjective lameness scores among treatments and over time. The full model included factors for treatment, time, and the treatment by time interaction. Multiple comparisons were adjusted by use of the Tukey test. An unstructured covariance model was used in all repeated-measures models. All hypothesis tests were 2 sided. Values of P < 0.05 were considered significant. The repeated-measures analysis was performed by use of statistical software.e
Results
Animals—No adverse effects or changes were detected during the study in any of the dogs. The body weight of each dog varied < 2% during the study. All dogs had consistent mild to moderate lameness after sodium urate injection and no treatment; however, none of the dogs was removed from the study because of signs of excessive pain or discomfort.
Lameness scores—For the negative control treatment, scores were significantly higher at 2, 4, 6, and 8 hours, compared with baseline scores (Figure 1). The perzinfotel treatment had significantly higher scores at 2, 4, and 6 hours, compared with baseline scores. The PLA2 inhibitor treatment had significantly higher scores at 2 and 4 hours, compared with baseline scores. There were no significant differences between baseline scores and scores at any time point for the positive control treatment. Between-treatment comparisons revealed that the PLA2 inhibitor treatment had significantly lower scores than did the negative control treatment at 2 hours. The positive control treatment had significantly lower lameness scores at 2, 4, and 6 hours, compared with lameness scores for the negative control and perzinfotel treatments.
Mean ± SEM cumulative lameness scores for dogs with sodium urate-induced synovitis in each of 4 treatment groups (n = 8 dogs/treatment). In a crossover design, dogs received perzinfotel (10 mg/kg [gray squares]), a proprietary PLA2 inhibitor (10 mg/kg [triangles]), carprofen (4.4 mg/kg; positive control treatment [black squares]), or no treatment (negative control treatment [diamonds]) once daily for 3 days. On the fourth day after initiation of treatment, synovitis was induced via intra-articular injection of sodium urate 1 hour before administration of the last treatment dose. The time point immediately before urate injection was designated as time 0 (baseline). There was a 21-day washout period between subsequent treatments. *Within the negative control treatment, the value differs significantly (P < 0.05) from the baseline value. †Within the PLA2 inhibitor treatment, the value differs significantly (P < 0.05) from the baseline value. ‡Within the perzinfotel treatment, the value differs significantly (P < 0.05) from the baseline value. §Within a time point, the value for the carprofen treatment differs significantly (P < 0.05) from the value for the negative control treatment. ||Within a time point, the value for the carprofen treatment differs significantly (P < 0.05) from the value for the perzinfotel treatment. ¶Within a time point, the value for the PLA2 inhibitor treatment differs significantly (P < 0.05) from the value for the negative control treatment.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
PVF—Compared with baseline values, the negative control and perzinfotel treatments had significantly lower PVFs at 2 and 4 hours (Figure 2). No significant differences from baseline values were detected for the PLA2 inhibitor or positive control treatments at any time point. Between-treatment comparisons revealed that the positive control treatment had significantly higher PVFs than did the negative control and perzinfotel treatments at 2 and 4 hours. The PLA2 inhibitor treatment had a higher PVF at 2 hours, compared with the PVF for the negative control treatment.
Mean ± SEM PVF for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). Results are reported as a percentage of body weight (% BW). See Figure 1 for key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
VI—Compared with baseline values, the negative control and perzinfotel treatments had significantly lower VI values at 2 and 4 hours (Figure 3). The PLA2 inhibitor group had a significantly lower VI value at 2 hours, compared with the baseline value. No significant differences from baseline values were detected for the positive control treatment at any time point. Between-treatment comparisons revealed that the positive control treatment had significantly higher VI values than did the negative control and perzinfotel treatments at 2 and 4 hours. The PLA2 inhibitor treatment had a higher VI value at 2 hours, compared with the VI value for the negative control treatment.
Mean ± SEM VI for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). Results are reported as a percentage of body weight times second. See Figures 1 and 2 for key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
PCBF—Compared with baseline values, the negative control and perzinfotel treatments had significantly lower PCBFs at 2 and 4 hours (Figure 4). No significant differences from baseline PCBFs were detected for the PLA2 inhibitor treatment or positive control treatment at any time point. Between-treatment comparisons revealed that the positive control treatment had significantly higher PCBFs at 2 and 4 hours, compared with the PCBFs for the negative control treatment.
Mean ± SEM PCBF for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). See Figures 1 and 2 for key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
CBI—The only change in CBI values from baseline values was a significant decrease for the negative control treatment at 2 hours (Figure 5). The only between-treatment difference was a significantly higher CBI value at 4 hours for the positive control treatment, compared with the CBI value for the negative control treatment.
Mean ± SEM CBI for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). See Figures 1 and 2 for key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
PCPF—Compared with baseline values, the perzinfotel treatment had significantly lower PCPFs at 2 and 4 hours (Figure 6). Between-treatment comparisons revealed that the PLA2 inhibitor treatment had significantly higher PCPFs than did the negative control and perzinfotel treatments at 4 hours. The positive control treatment had a significantly higher PCPF at 2 hours, compared with the PCPF for the negative control treatment.
Mean ± SEM PCPF for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). §Within a time point, value for the PLA2 inhibitor treatment differs significantly (P < 0.05) from the value for the perzinfotel treatment. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
CPI—Compared with baseline values, the negative control treatment had a significantly lower CPI value at 2 hours and perzinfotel had a significantly lower CPI value at 4 hours (Figure 7). Between-treatment comparisons revealed that the PLA inhibitor and positive control treatments had significantly higher CPI values than did the negative control treatment at 2 hours.
Mean ± SEM CPI for dogs with sodium urate–induced synovitis in all 4 treatments (n = 8 dogs/treatment). See Figures 1 and 2 for key.
Citation: American Journal of Veterinary Research 72, 6; 10.2460/ajvr.72.6.757
Discussion
The sodium urate–induced synovitis technique used in the study reported here resulted in a consistent mild to moderate lameness, as determined by use of the subjective lameness scoring system. With this subjective instrument, the lameness was significantly evident for 8 hours, compared with baseline scores. Interestingly, when examining the same dogs with objective vertical GRF measurements, a consistent lameness was only detectable for the first 4 hours after sodium urate injection. Therefore, the technique was reliable for inducing changes in lameness for a short period, depending on the measurement used. Results of both evaluation methods revealed that dogs were beginning to return to baseline values within 6 hours after sodium urate injection and were completely back to baseline values by 12 hours. The sodium urate dose used in the present study induced a much less severe lameness than did higher urate doses described in other studies.6,26,27
It was interesting that subjective evaluations detected lameness at 8 hours, but evaluation of GRFs only detected a consistent lameness for the first 4 hours. It would not be expected that a subjective instrument would be more sensitive than an objective gait analysis, and this finding is not consistent with results in other reports6,26,27 in which investigators used the sodium urate-induced synovitis technique. One possible explanation for these data is that the observers were biased in their belief that the dogs should be lame for a longer time on the basis of the results reported in the literature for the sodium urate–induced synovitis technique.
The inclusion of a placebo (no treatment) group is often controversial in the evaluation of pain. However, with new unproven analgesic agents, it is necessary to know whether these agents are comparable to a proven analgesic (eg, an NSAID or opioid). They may also have significant effects (which may not be as strong as a positive control treatment), compared with baseline values. As stated previously, the sodium urate–induced synovitis technique used in the present study provided short-term mild to moderate lameness and differences in analgesia attributable to the agents could be identified.
Perzinfotel did not result in significant attenuation of limb dysfunction caused by the sodium urate–induced synovitis. The differences detected by use of subjective and objective evaluation methods between perzinfotel and the negative control treatment were subtle. In view of previous clinical evidence that indicated analgesic activity of perzinfotel,2,11,15 the lack of an effect in the study reported here was surprising. However, the lack of efficacy of perzinfotel for the sodium urate–induced synovitis technique may be explained by several mechanisms. First, this failure may simply have been attributable to a dose-dependent response (ie, the dose given in this study was insufficient to attenuate lameness in the dogs). Second, perzinfotel was administered to dogs once daily for 3 days prior to sodium urate injections, with a final dose of perzinfotel administered 1 hour after sodium urate injection. Therefore, it is not known whether the once-daily dosing had any preemptive effect on central sensitization in these dogs. It is possible that the 1-hour interval between the sodium urate injection and administration of perzinfotel allowed sufficient time for central sensitization to develop, thereby decreasing potential effects of the perzinfotel. In another study,12 epidural administration of ketamine, a nonselective NMDA receptor inhibitor, had no effect when given 12 hours after sodium urate–induced synovitis but resulted in improvement of GRF at 2 hours after induction of synovitis when administered at the same time as the sodium urate. Timing of perzinfotel administration relative to application of noxious stimuli may also be important for achieving the desired effect of decreased hypersensitivity. Lack of an effect of perzinfotel in the present study may also have been attributable to the selectivity of perzinfotel for the glutamate site of the NR2A subunit.11 The NR2A-containing NMDA receptors are not present on the presynaptic primary afferent fibers in the dorsal root ganglion of rats.16,20 Substance P, prostaglandins, adenosine, and glycine as well as glutamate (which can enhance its own release) can be released from the presynaptic afferent fibers and act on presynaptic and postsynaptic receptors.3,13,16 Stimulation of presynaptic NR2B-containing NMDA receptors can facilitate and prolong transmission of nociceptive messages.16 It has also been reported that NR2A–knockout mice failed to have changes in acute and chronic pain-related behaviors.16 Substance P and glutamate release cause influx of Ca2+ and Na+ with resultant activation of protein kinase C,3 which drives tyrosine phosphorylation of the NMDA receptors.20 This causes release of Mg2+, which acts to block NMDA receptors, thus decreasing resting membrane potential and allowing for a prolongation of channel-opening time.20 The end result is increased postsynaptic activity caused by the multiplicity of neurotransmitters in the dorsal root ganglion synapses. These processes may have allowed the perzinfotel-treated dogs in the study reported here to continue to have evidence of lameness and signs of pain. Finally, another possible reason is that similar to other NMDA receptor antagonists, perzinfotel has not been found to have antinociceptive effects; rather, it has prevented hypersensitivity, as was reported in another study.11 Specifically, NR2A appears to play a larger role than does NR2B in inflammatory states, with upregulation of the NR2A subunits in areas of the brain and spinal cord as a result of peripheral inflammatory stimuli.11 Spinal cord NR2A subunits have been decreased in evaluations of experimentally induced nerve pain.11 Perzinfotel may play an important role in analgesia when used synergistically with opioids or NSAIDs.3,15
The PLA2 inhibitor attenuated lameness at both time points at which the negative control values were different from baseline values. Interestingly, at no time point in the study was a difference between the PLA2 inhibitor and the positive control treatment (administration of carprofen) detectable by use of the subjective or objective measurements. Almost all the measurements indicated the results for the PLA2 inhibitor were between those for perzinfotel and carprofen. However, attenuation of lameness by the PLA2 inhibitor was not as complete as that for carprofen. The effectiveness of the PLA2 inhibitor used in the present study may have been related to its inhibition of the metabolism of arachidonic acid to subsequent eicosanoids and resultant anti-inflammatory effects. Phospholipase A2, as a superfamily, has been found to be involved in many functions, including antimicrobial activity, bone formation, apoptosis, insulin secretion, spermatozoa development, Wallerian degeneration, and axon regeneration as well as serving as a marker of coronary disease in humans and as an anti-inflammatory agent.21,28 Of the 4 main types of PLA2 (secreted, cytosolic, calcium independent, and platelet-activating factor acetyl hydrolase and oxidized lipid protein associated), cytosolic PLA2 (particularly calcium-dependent PLA2) is a central enzyme that mediates generation of eicosanoids and subsequent inflammatory processes.21 In addition, cytosolic PLA2 has a role in neurotransmitter release by coupling with a multitude of receptors (eg, glutamate, dopamine, and serotonin) in the brain.18 A constitutive spinal PLA2 has been detected in rats and monkeys.25 Although numerous cytosolic PLA inhibitors with enzymatic activity have been evaluated, many have no in vivo effect.19 It appears that the PLA2 inhibitor used in the present study performed comparably to the positive control treatment (ie, carprofen) in the sodium urate-induced synovitis method for evaluating pain attributable to inflammation.
Phospholipase A2 receptor antagonists have a dose-dependent association with the outcome measures of antihypersensitivity effects and prostaglandin E2 production.19 As clinical trials are conducted to evaluate the analgesic effects of these compounds and effective PLA2 receptor antagonists are identified, appropriate dosing regimens and safety margins will need to be established, along with drug interactions. To our knowledge, there have been no listed adverse effects of these compounds, although there is a report29 of a human deficient in cytosolic PLA2-α who developed ulcers in the small intestines and platelet dysfunction. It is interesting that opioids stimulate PLA2 in presynaptic afferent fibers, which leads to formation of metabolites of 12-lipoxygenase.1 These metabolites enhance the activity of voltage-dependent K+ channels, which inhibit γ-aminobutyric acid—mediated neurotransmission.1 Use of COX-1, COX-2, and specific 5-lipooxygenase inhibitors shunt more metabolites to the 12-lipooxygenase pathway, which synergistically enhances the μ-opioid–based release of γ-aminobutyric acid.30 Phospholipase A2 receptor antagonists can block this μ-opioid effect.30 Concurrent use of PLA2 receptor antagonists and μ-opioids in a clinical setting may be contraindicated, but PLA2 receptor antagonists appear to have merit for use in analgesia.
ABBREVIATIONS
| CBI | Craniocaudal braking impulse |
| COX | Cyclooxygenase |
| CPI | Craniocaudal propulsion impulse |
| GRF | Ground reaction force |
| NMDA | N-methyl-d-aspartate |
| PCBF | Peak craniocaudal braking force |
| PCPF | Peak craniocaudal propulsion force |
| PLA2 | Phospholipase A2 |
| PVF | Peak vertical force |
| VI | Vertical impulse |
Randomization plan generator. Available at: www.randomization.com. Accessed Dec 14, 2009.
PLA-695, Fort Dodge Animal Health, Princeton, NJ.
Model OR-6-6, Advanced Mechanical Technology Inc, Newton, Mass.
Acquire, version 7.3, Sharon Software, East Lansing, Mich.
PROC MIXED, SAS, version 9.2, SAS Institute Inc, Cary, NC.
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Appendix
Description of a scale used for subjective clinical lameness evaluation of dogs with sodium urate–induced synovitis of a stifle joint.
| Variable | Score | Description |
|---|---|---|
| Stance | 0 | Normal stance |
| 1 | Slightly abnormal stance (favors limb but foot remains on ground) | |
| 2 | Severely abnormal stance (holds limb off of ground) | |
| 3 | Not able to stand | |
| Lameness at a walk | 0 | No lameness and full weight bearing observed on all strides; gait is not affected |
| 1 | Mild subtle lameness with partial weight bearing; may bear full weight on some strides but not on other strides | |
| 2 | Obvious lameness with partial weight bearing; clearly lame on all strides | |
| 3 | Obvious lameness with intermittent weight bearing; non-weight bearing on some strides but partial weight bearing on other strides (includes slight lameness [ie, toe touching] on some strides) | |
| 4 | Full non-weight-bearing lameness; bears no weight on any strides | |
| Lameness at a trot | 0 | No lameness and full weight bearing observed on all strides; gait is not affected |
| 1 | Mild subtle lameness with partial weight bearing; may bear full weight on some strides but not on other strides | |
| 2 | Obvious lameness with partial weight bearing; clearly lame on all strides | |
| 3 | Obvious lameness with intermittent weight bearing; non-weight bearing on some strides but partial weight bearing on other strides (includes slight lameness [ie, toe touching] on some strides) | |
| 4 | Full non-weight-bearing lameness; bears no weight on any strides | |
| Signs of pain on manipulation of affected joint through range of motion | 0 | No signs of pain elicited on palpation or movement of affected joint |
| 1 | Signs of mild pain elicited (turns head in recognition) on palpation or movement of affected joint | |
| 2 | Signs of moderate pain elicited (pulls limb away) on palpation or movement of affected joint | |
| 3 | Signs of severe pain elicited (vocalizes or becomes aggressive; does not allow palpation or movement of affected joint) on palpation or movement of affected joint |
(Adapted from Cross AR, Budsberg SC, Keefe TJ. Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate–induced synovitis model in dogs. Am J Vet Res 1997;58:626–631. Reprinted with permission.)
