Impairment in locomotor activity as an objective measure of pain and analgesia in a rat model of osteoarthritis

Abstract

A major problem with current animal models of pain is their lack of face validity and their vulnerability for false positive results. The present study evaluated the efficacy of the open field locomotor system, as an objective measure of pain-related behavior and analgesic efficacy in rodents. Adult, male, Sprague-Dawley rats (180-250 g) received intra-articular injections of monoiodoacetate (MIA; 1 mg) in the left knee joint. Mechanical allodynia using von Frey filaments, the weight bearing difference test and the open field locomotor activity test were performed every other day for 21 days, following the MIA injection. The antinociceptive effects of ibuprofen (50 and 100 mg/kg) on the MIA-induced nociception were also evaluated. MIA induced a significant reduction in the paw withdrawal threshold (PWT) and a significant alteration in the weight bearing difference compared with control rats. Similarly, MIA induced a significant reduction in locomotor activity, with respect to X total counts, that represent the overall locomotor activity in the horizontal plane, and X ambulatory counts, which in turn represent small scale movements, such as scratching and grooming, and lastly, Z total counts, that represent rearing or standing. Both doses of ibuprofen resulted in a significant reversal of the MIA-induced alterations in PWT and weight bearing difference. Furthermore, the two doses of ibuprofen resulted in a significant reversal of the MIA-induced reduction in locomotor activity, with respect to X ambulatory counts, but not Z total counts. Only the higher dose of ibuprofen reversed the X total counts. The open field locomotor system may successfully be used to predict the analgesic efficacy of compounds in models of joint inflammation and osteoarthritis.

Keywords: antinociception; ibuprofen; locomotion; osteoarthritis; pain; rat.

Figure 1

Effects of intra-articular injection of MIA or vehicle (3% Tween-20 in saline) on mechanical allodynia in rats. (A) Ratio of the left hind paw contribution in total weight bearing (L/L+R). (B) Mechanical PWT was measured in grams. Data are presented as the mean ± SEM of n=6 rats. Data was analyzed using two-way ANOVA with Holm Sidak post hoc test. ^*P<0.05 vs. day 0; ^#P<0.05 vs. saline group. L, amount of weight bearing in the left hind paws in grams; R, amount of weight bearing in the right hind paw in grams; MIA, monoiodoacetate; PWT, paw withdrawal threshold.

Figure 2

Effects of intra-articular injection of MIA or vehicle (3% Tween-20 in saline) on locomotor activity in rats. (A) X total counts. (B) X ambulatory counts. (C) Z total counts. A significant reduction was observed in X total and ambulatory counts, while the reduction of Z total counts persisted from day 5 to day 13 in MIA-treated compared with that in the vehicle-treated rats. Data are presented as the mean ± SEM of n=6 rats. Data was analyzed using two-way ANOVA with Holm Sidak post hoc test. ^*P<0.05 vs. day 0; ^#P<0.05 vs. saline group. MIA, monoiodoacetate.

Figure 3

Effects of ibuprofen (50 and 100 mg/kg) or vehicle (3% Tween-20 in saline) on MIA-induced mechanical allodynia in rats. The rats received an intraperitoneal injection of ibuprofen or vehicle at day 7, following MIA injection. Alterations in (A) the left hind paw contribution in total weight bearing and (B) PWT, 1 h post drug injection. Data are presented as the mean ± SEM of percentage antinociception. n=5 rats for the control group and n=6 rats for each of the treated groups (50 and 100 mg/kg). Data was analyzed using one way ANOVA followed by Bonferroni post hoc test. ^*P<0.05. MIA, monoiodoacetate; PWT, paw withdrawal threshold.

Figure 4

Effects of ibuprofen (50 and 100 mg/kg) or vehicle (3% Tween-20 in saline) on MIA-induced alterations in locomotor activity. The rats received an intraperitoneal injection of ibuprofen or vehicle at day 7, following MIA injection. (A) X total counts. (B) X ambulatory counts. (C) Z total counts. Data are presented as the mean ± SEM of percentage locomotor activity recovery. n=5 rats for the control group and n=6 rats for each of the treated groups (50 and 100 mg/kg). Data was analyzed using one-way ANOVA followed by Bonferroni post hoc test. ^*P<0.05. MIA, monoiodoacetate.