Representative tracings of horizontal locomotor activity from a 30-minute period during the dark phase (2000-2030 hours) are shown in Figure 3. Visually significant reductions in horizontal activity are apparent on days 1 and 3 in the open field apparatus when compared with naive baseline and with day 12.
The numbers of vertical rearing episodes among the different observation days were significantly different (F(4,91) = 20.79; P < 0.0001; 2-factor ANOVA, followed by Tukey multiple comparisons test) (Fig. 4A–D). There were significant reductions in rearing episodes on days 1 and 3 after orthopedic surgery at the first hour of exploratory behavior (hour 1 baseline = 205.3 ± 14.9; hour 1 day 1 = 130.4 ± 13.4 [P = 0.0005]; hour 1 day 3 = 129.0 ± 14.0 [P = 0.0005]; 1-factor ANOVA, followed by Tukey multiple comparisons) and most hours during the dark phase (Fig. 4A, B and E, respectively). On day 7 after orthopedic surgery, there was no significant reduction in the number of rears at the first hour of exploratory behavior (Fig. 4E). However, as with distance traveled, at various hours during the dark phase, there remained a significant reduction in rears (Fig. 4C). By day 12 after orthopedic surgery, all activity time points have returned to baseline values (Fig. 4D and E). There were no significant differences (P > 0.05; 1-factor ANOVA, followed by Tukey multiple comparisons) in locomotor activity during the light phase after the initial exploratory hour when compared among the different observational periods (Fig. 4F).
The overall horizontal average velocity of locomotor activity among the different observation days was significantly different (F(4,91) = 10.77; P < 0.0001; 2-factor ANOVA, followed by Tukey multiple comparisons test) (Fig. 5A–D). There was no significant reduction in horizontal average velocity on days 1 and 3 after orthopedic surgery at the first hour of exploratory behavior (hour 1 baseline = 7.2 ± 0.2 cm/s; hour 1 day 1 = 7.3 ± 0.3 cm/s [P = 0.775]; hour 1 day 3 = 7.1 ± 0.3 cm/s [P = 0.831]; 1-factor ANOVA, followed by Tukey multiple comparisons test) (Fig. 5E), but there was a significant increase in horizontal velocity on day 7 after orthopedic surgery at the first hour of exploratory behavior (hour 1 day 7 = 8.3 ± 0.2 cm/s [P = 0.01]; 1-factor ANOVA, followed by Tukey multiple comparisons test; Fig. 5E). By day 12 after orthopedic surgery, all activity time points have returned to baseline values (Fig. 5D and E). There were no significant differences (P > 0.05; 1-factor ANOVA, followed by Tukey comparisons test) in horizontal average velocity during the light phase after the initial exploratory hour when compared among the different observational periods (Fig. 5F).
To better visualize the differences in peak nocturnal activity between the baseline and postinjury observation periods, the areas under the time-effect curves were measured between 1900 and 2200 hours. Nocturnal horizontal average velocity was significantly (F(4,91) = 9.528; P < 0.0001; 1-factor ANOVA, followed by Tukey multiple comparisons test) reduced from baseline on days 1 and 3 but not on days 7 and 12 (Fig. 5G; AUC baseline = 21 ± 0.38, AUC day 1 = 17 ± 0.72, AUC day 3 = 19 ± 0.57, AUC day 7 = 20 ± 0.58, and AUC day 12 = 22 ± 0.52 cm/s).
Animals were preemptively treated with an antibody against NGF administered 7 and 2 days before orthopedic surgery. Animals treated with anti-NGF exhibited significantly greater horizontal activity on days 1 (t(14) = 2.799; P = 0.0142) and 3 (t(14) = 3.162; P = 0.0069) after orthopedic surgery during the initial exploratory hour when compared with vehicle-treated animals (Fig. 6A; vehicle day 1 = 2110 ± 564 cm, anti-NGF day 1 = 4235 ± 506 cm; vehicle day 3 = 1979 ± 568 cm, and anti-NGF day 3 = 3824 ± 269 cm). The number of vertical rearing episodes after anti-NGF treatment on days 1 and 3 after orthopedic surgery during the initial exploratory hour was also significantly increased when compared with that after vehicle treatment (Fig. 6C; vehicle day 1 = 114 ± 27.0, anti-NGF day 1 = 189 ± 22.4; t(14) = 2.165, P = 0.0481; vehicle day 3 = 110 ± 24.3, anti-NGF day 3 = 171 ± 15.8; t(14) = 2.199, P = 0.0452). Animals treated with anti-NGF exhibited an increase in horizontal velocity on days 1 and 3 after orthopedic surgery during the initial exploratory hour compared with vehicle-treated animals, but the effect was not significant (Fig. 6E; vehicle day 1 = 6.33 ± 0.386 cm/s, anti-NGF day 1 = 6.66 ± 0.327 cm/s; t(14) = 0.6576, P = 0.5214; vehicle day 3 = 6.43 ± 0.571 cm/s, anti-NGF day 3 = 7.17 ± 0.348 cm/s; t(14) = 1.15, P = 0.2693).
Animals treated with anti-NGF exhibited significantly higher horizontal activity on day 1 after orthopedic surgery during peak nocturnal activity (1900-2200 hours) compared with vehicle-treated animals (Fig. 6B; vehicle day 1 = 2611 ± 495 cm, anti-NGF day 1 = 6964 ± 1626 cm; t(14) = 2.281, P = 0.0387). The number of vertical rearing episodes after anti-NGF treatment during peak nocturnal activity increased when compared with that after vehicle treatment, but the effect was not significant (Fig. 6D; vehicle day 1 = 196.3 ± 45.6, anti-NGF day 1 = 397.3 ± 94.9; t(14) = 1.741, P = 0.1036). However, as with horizontal activity, animals treated with anti-NGF exhibited a significant increase in horizontal velocity on day 1 after orthopedic surgery during peak nocturnal activity compared with vehicle-treated animals (Fig. 6F; vehicle day 1 = 16.0 ± 0.9 cm/s, anti-NGF day 1 = 20.5.8 ± 1.0 cm/s; t(14) = 3.225, P = 0.005). On day 3 after orthopedic surgery, during peak nocturnal activity (1900-2200 hours), animals treated with anti-NGF exhibited increased horizontal activity, vertical rearing, and horizontal velocity compared with vehicle-treated animals, but the increases were not significant.
Acute and chronic human skeletal pain remains a difficult pain to fully control using currently available analgesics.16,52,81 In light of this significant unmet clinical need, several preclinical rodent models have been developed.3,4,7,49,54,59,65,72,82 While many of these preclinical rodent models of skeletal pain mirror the bone or joint pathology that drives human skeletal pain, there are several major challenges in behaviorally assessing pain and analgesia in these models.
The first major problem in measuring pain in rodent preclinical models is that in most cases, the behaviors are performed during daylight hours (7 AM-7 PM) which is the time that rodents are normally least active or sleeping.23,30,37,39,41,81 As human clinical trials examining the efficacy of an analgesic on relieving skeletal pain usually focus on when the patient is normally awake, and not when they are sleeping, it is not clear how one can readily translate results obtained from rodents during the time when the animal is least active vs assessments conducted when humans are normally most active.
A second major problem with current assessments of rodent skeletal pain behaviors is that nearly all rodent pain behaviors are evoked and not spontaneous. For example, currently, the most commonly used endpoint in skeletal pain behaviors is skin hypersensitivity as assessed by von Frey (mechanical testing) or the Hargreaves method (thermal).2,20,51,67 While it may be peripheral and/or central sensitization15,21,29,50,60,64 that is driving this skeletal injury–induced skin hypersensitivity, from the perspective of a patient with skeletal pain due to OA or TKA/THA, evoked skin hyperalgesia is rarely the major pain complaint.18,55,62 Rather, the major complaint of patients with orthopedic surgery pain is the spontaneous pain that arises upon use of the bone/joint that interferes with their quality of life, functional status, and ability to participate in the needed physical therapy and rehabilitation.10 Indeed, it has recently been questioned whether analgesics that relieve skin hypersensitivity accurately predicts the extent to which the analgesic will also reduce the underlying skeletal pain28,70 and at the very least, it is not clear how one would design, perform a power analysis, or determine what endpoints would be measured in a human clinical trial that is based principally on the ability of an analgesic to relieve skin hypersensitivity.
Third, even when “skeletal pain related behaviors” such as limb guarding, flinching, or weight bearing are assessed, these behaviors are evoked in that the animal is removed from its home cage during their normal sleep period and their behaviors assessed during the least active period of the animal's day.23,30,37,39,41,81 Equally important, all observer-based assessments of pain are subject to unavoidable observer differences and bias.74,76 Thus, what is a guard or flinch to 1 observer may be scored differently by another observer. In addition, when the analgesic therapy under examination has either a large therapeutic effect or a noticeable side effect, it becomes even more difficult to fully remove observer bias.
In light of the above challenges, in the present report, day/night horizontal activity, horizontal velocity, and episodes of vertical rearing were assessed in mice with orthopedic surgery–induced skeletal pain. The animals were continuously monitored for a 20-hour period before orthopedic surgery and then at days 1, 3, 7, and 12 after surgery using a system that continually measures spontaneous locomotion and hindlimb rearing for precise analysis of circadian patterns. At days 1 and 3 after orthopedic surgery, mice showed a marked decline in horizontal activity and vertical rearing. In all the mice, activity was greatest during the first 30 minutes they were placed in the activity boxes (the exploratory period) and for the first 3 hours after the onset of the dark cycle (peak night activity). Interestingly, it was during these times when the animals were most active that one observes the greatest differences between the naive animals and animals that had orthopedic surgery. At other periods, during both the day and night, when the animals were less active and there was less spontaneous rearing, very small or no significant differences were noted between naive animals and animals that had orthopedic surgery.
The present results clearly show that there are significant differences in horizontal activity and vertical rearing episodes in C3H mice at days 1 and 3 after orthopedic surgery vs their baseline behaviors. In contrast, by days 7 and 12 after surgery, these differences are largely gone, presumably due to healing of the injured skeleton. However, there are several additional controls/experiments that may provide insight into the strengths and limitations of using mouse activity to measure orthopedic surgery–induced pain. These include the following: testing a nonsurgical group at the identical time as the animals which had orthopedic surgery, running a sham group which had only a skin incision, and identifying and using a strain of mice that may have significantly higher baseline activity than the C3H mice used in the present experiments.22 Experiments do suggest that naive C3H mice do not appreciably change their horizontal activity or vertical rearing over a 14-day observation period (unpublished observations) and skin incision alone does not induce significant changes in skeletal pain behaviors measured by guarding and flinching.49 However, running these additional controls and strains of mice on the same day, in the same 20-hour activity apparatus used here, has the potential to better define the strengths and weaknesses of using activity boxes to measure skeletal pain and assessing the efficacy of analgesics in relieving skeletal pain.
Spontaneous movement has been validated and successfully used as an outcome measure in cat26,27 and dog11–14,61,78,80 spontaneous models of chronic OA musculoskeletal pain, and it is well established that activity is an important measure of musculoskeletal pain–associated disability in humans.9,35,43,58,73 Similarly, with skeletal pain following orthopedic surgery, our data indicate that mice show a marked reduction in levels of spontaneous movement and rearing and thus have significantly reduced “functional status” compared with their nonoperated controls. The present data also emphasize the importance that, just as in humans with skeletal pain, focusing on measuring spontaneous activity-based behaviors during the period when the animal or human is most active greatly improves the ability to capture the reduction in functional status which is the hallmark in animals and humans with chronic skeletal pain.
In exploring possible alternatives to NSAIDs or opiates to control postoperative orthopedic surgery pain, we focused on anti-NGF.16,23,30,38,39,41,45,47,52 Previous studies in humans with OA and low back pain showed that anti-NGF reduced these skeletal pains by 40% and 30%, respectively,40,45 and dramatic improvement in function and activity was seen in cat27 and dog47 spontaneous OA models after administration of anti-NGF. In this study, during the times the animals were most active, anti-NGF increased horizontal activity, velocity, and vertical rearing but had no effect in increasing activity or rearing when the mice were normally less active. Thus, anti-NGF seems to be relieving skeletal pain, which results in increased use of the skeleton, rather than simply driving a hyperlocomotion which would boost the activity at all day and nighttime points examined. The present results also suggest that human clinical trials targeting the relief of orthopedic surgery pain including that due to TKA or THA may be a fruitful approach in gaining approval of anti-NGF and TrkA inhibitors for human skeletal pain. Thus, the time needed to assess analgesic efficacy and the surveillance period for unwanted side effects would be weeks/months for TKA or THA rather than months to years required for OA and low back pain.
The present results in mice may shed some light on an issue that was raised in human clinical trials of anti-NGF for the relief of OA pain.1 In these human studies, although it was shown that anti-NGF therapy was efficacious in relieving pain due to OA, a small but significant number of elderly (>65 years old) patients with moderate-to-severe OA pain on the highest dose of anti-NGF and an NSAID needed earlier-than-expected joint replacement.33,45 In light of these results, it was not clear whether this earlier-than-expected joint replacement was due to greater use of the diseased joint (ie, excessive use and loading of the bone or joint)36 or a direct and delirious effect anti-NGF plus the NSAID were having on the bone or joint.52 The present data demonstrate that in a mouse model of orthopedic surgery pain, anti-NGF does increase activity and rearing in animals with the injured skeleton, suggesting that monitoring and advising patients as to the overuse of their skeleton may minimize the orthopedic surgeries required to repair excessive use–induced injury to the aging/diseased bone and joint.
The authors have no conflicts of interest to declare.
This research was funded by NIH Grants CA154550, CA157449, and NS023970 to Patrick Mantyh. The anti-NGF used in this study was a kind gift from Drs. Kris Poulsen and David Shelton (Rinat/Pfizer, San Francisco, CA). P. W. Mantyh has served as a consultant and/or received research grants from Abbott (Abbott Park, IL), Adolor (Exton, PA), Array BioPharma (Boulder, CO), Johnson and Johnson (New Brunswick, NJ), Merck (White Plains, New York), Pfizer (New York, NY), Plexxikon (Berkeley, CA), Rinat (South San Francisco, CA), and Roche (Palo Alto, CA).
The authors thank Michelle Thompson, Alec Calac, Natalie Hamdan, Logan Moore, and Sabrina Rivas for their help with preoperative/postoperative surgical care and activity box maintenance. They also thank Kirsten Raehal and Tonja Burshek from Mycrosite (Ft Collins, CO) for their invaluable advice on the set-up and maintenance of the activity boxes.
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