Sensory and vascular changes in a rat monoarthritis model: prophylactic and therapeutic effects of meloxicam

Abstract

Objective and design: The objective of this study was to determine the ability of meloxicam prophylaxis and therapy to blunt the effect of complete Freund's adjuvant (CFA) induced monoarthritis.

Materials and methods: First the validity of this animal model was established by examining joint changes at multiple levels after injecting CFA into the tibio-tarsal joint. Next, meloxicam (5 mg/kg) or vehicle was administered on days 0-7 (prophylactic) and on days 7-16 (therapeutic) in separate groups of animals.

Results: The CFA-injected joint demonstrated hallmark histological and structural changes such as pannus formation, bone remodeling, cartilage erosion and immune cell infiltration. Both prophylactic and therapeutic treatment with meloxicam effectively reduced swelling (ankle circumference), oedema and extravasation of Evans blue dye in the affected joint. Moreover, meloxicam reduced loss in range of motion and also reduced mechanical stimulus evoked pain scores. Notably, these effects persisted after discontinuing drug treatment.

Conclusion: The present study provides a unique comparison of prophylactic versus therapeutic effects of meloxicam in the CFA-induced model of monoarthritis.

Fig. 1

Photomicrographs of H&E stained sagittal sections of the tibio-tarsal joint of untreated (a) and CFA-injected (b) rats. Each scale bar represents 100 μm. a Normal tibio-tarsal joint demonstrating the articulation of the distal tibia and the proximal tarsus with the synovial membrane (at arrow 1). b Synovial membrane inflamed and hyperplastic (at arrow 1). c Inflammatory cells observed in the sub synovial region showing infiltration with lymphocytes, macrophages, neutrophils and myofibroblasts indicated by arrows 1–4 respectively. d Pannus extending into the joint space and infringing on articular cartilage (at arrows 1 & 2 respectively). e Osteophyte forming in the tarsal bone (at arrow 1). f Osteophyte presented in e at a higher magnification. g Fibrin exudation from the synovial membrane indicating erosion of synovium

Fig. 2

Three-dimensional reconstructions of micro-computed tomographic images obtained from the tibio-tarsal joint of control rats (a, c) and CFA-injected rats (b, d), obtained with a micro-CT scanner. CFA-induced abnormal changes in bone structure, bone remodeling with osteophytes formed extensively in CFA-treated animals. Arrows in d illustrate the following: 1 osteoporosis observed as increased lucency in the cortices of the bones, 2 reduction in joint space associated with loss of cartilage and changes in bone alignment, 3 osteophyte or new bone forming on the bone surfaces

Fig. 3

Effects of meloxicam on range of motion of the CFA injected joint. a Effects of CFA or saline on ankle range of motion. b, c Effects of Meloxicam (filled square) or vehicle (0.5% methylcellulose; filled diamond) administration on days 0–7 (b), or on days 7–16 (c) on range of motion in the CFA injected joints. Black horizontal bars indicate the days of drug administration. Measurements from four rats from each group were obtained on given days after drug treatment was discontinued. The data shown are the mean ± SEM. *p < 0.05 for comparisons between CFA injected rats with untreated rats or saline-treated rats (significant at all time points). *p < 0.05 significant for comparisons of CFA treated rats between meloxicam and vehicle treatment. ^†p < 0.05 for comparisons with pre-induction (day-0) values

Fig. 4

Effects of meloxicam on circumference of CFA injected joint. a Effects of CFA or saline on ankle circumference. b, c Effects of meloxicam (filled square) or vehicle (0.5% methylcellulose; filled diamond) administration on days 0–7 (b), or on days 7–16 (c) on circumference of the CFA injected joints. Black horizontal bars indicate the days of drug administration. Measurements from four rats from each group were obtained on given days after drug treatment was discontinued. The data shown are the ± SEM of means. *p < 0.05 for comparisons between CFA injected rats with untreated rats or saline-treated rats and also for comparisons of CFA treated rats between meloxicam and vehicle treatment. ^†p < 0.05 for comparisons with pre-induction (day-0) values

Fig. 5

Effects of CFA or saline injections in the ankle on plasma extravasation and oedema (a, b). Effects of meloxicam or vehicle (0.5% methylcellulose) administration on plasma extravasation (c, d) and oedema (e, f) for treatments given on days 0–7 or 7–16 in CFA injected joints. Black horizontal bars indicate the days of drug administration. The data shown are the ± SEM of means. *p < 0.05 for comparisons between CFA injected rats with untreated rats or saline-treated rats, and also for comparisons of CFA-treated rats between meloxicam and vehicle treatment. ^†(p < 0.05) for comparisons with values from naïve rats

Fig. 6

Effects of meloxicam on mechanical withdrawal thresholds of CFA-injected joint. a Effects of CFA or saline on mechanical withdrawal thresholds. b, c Effects of meloxicam (filled square) or vehicle (0.5% methylcellulose; filled diamond) administration on days 0–7 (b), or on days 7–16 (c) on mechanical withdrawal thresholds of CFA-injected joints. Black horizontal bars indicate the days of drug administration. Measurements from four rats from each group were obtained on given days after drug treatment was discontinued. The data shown are the ± SEM of means. *p < 0.05 for comparisons between CFA-injected rats with untreated rats or saline-treated rats and also for comparisons of CFA-treated rats between meloxicam and vehicle treatment. ^†(p < 0.05) for comparisons with pre-induction (day-0) values