Antinociceptive efficacy of lacosamide in the monosodium iodoacetate rat model for osteoarthritis pain - PubMed (original) (raw)

Comparative Study

Antinociceptive efficacy of lacosamide in the monosodium iodoacetate rat model for osteoarthritis pain

Bettina Beyreuther et al. Arthritis Res Ther. 2007.

Abstract

The etiology of osteoarthritis is multifactorial, with inflammatory, metabolic, and mechanical causes. Pain in osteoarthritis is initiated by mild intra-articular inflammation and degeneration of articular cartilage and subchondral bone. The principle of treatment with acetaminophen or non-steroidal anti-inflammatory drugs is to reduce pain and improve joint function. Recently, animal models for osteoarthritic pain behavior have been established. The most frequently used rat model for analyzing properties of drugs on the pathology of osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into the joint, which inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes. Here, we characterize the effect on pain behavior of lacosamide, a member of a family of functionalized amino acids that are analogues of endogenous amino acids and D-serine, in the monosodium iodoacetate rat model for osteoarthritis in comparison to diclofenac and morphine. Lacosamide (3, 10, and 30 mg/kg) was able to reduce secondary mechanical allodynia and hyperalgesia similarly to morphine (3 mg/kg). In contrast, diclofenac (30 mg/kg) was only effective in reducing secondary mechanical hyperalgesia. During the first week, pain is induced mainly by inflammation in the iodoacetate model, but afterwards inflammation plays only a minor role in pain. Lacosamide was able to inhibit pain at days 3, 7 and 14 after induction of arthritis. This shows that lacosamide is able to reduce pain behavior induced by multiple mechanisms in animals.

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Figures

Figure 1

Figure 1

Histological analysis of synovial tissue and articular cartilage pre- and post-monosodium iodoacetate (MIA) injection. Time course of histological changes of the rat knee before and days 3 and 14 after MIA injection. Left sections of the medial aspect of rat knee joints were stained with hematoxylin and eosin, right sections with safranin-O fast green. In non-arthritic rats no abnormality is present. On day 3 after MIA treatment the hematoxylin and eosin stained sections show significant expansion of the synovial membrane with a large amount of cellular infiltrate. No inflammation can be seen on day 14 post-MIA injection. The sections stained with safranin-O fast green reflect major cartilage degeneration on day 14 post-MIA injection. SM, synovial membrane; FE, femur; TI, tibia.

Figure 2

Figure 2

Effect of lacosamide and morphine on tactile allodynia after monosodium iodoacetate (MIA) injection. Effect of lacosamide and morphine on paw withdrawal threshold in the von Frey filament test in iodoacetate-treated animals on (a) day 3, (b) day 7 and (c) day 14 after arthritis induction. Rats were tested 45 to 60 minutes post-drug. Data from 12 animals/group are presented as mean ± SEM. *P < 0.05 Dunnett's test versus MIA/vehicle treated animals.

Figure 3

Figure 3

Effect of diclofenac on tactile allodynia after monosodium iodoacetate (MIA) injection. Effect of diclofenac on paw withdrawal threshold in the von Frey filament test in iodoacetate-treated animals on days 3, 7 and 14 after arthritis induction. Rats were tested 45 to 60 minutes post drug. Data from12 animals/group are presented as mean ± SEM. *P < 0.05 Dunnett's test versus MIA/vehicle treated animals.

Figure 4

Figure 4

Tactile allodynia measurement in normal rats after lacosamide treatment. Effect of lacosamide on paw withdrawal threshold in the von Frey filament test in saline treated normal rats. Rats were tested 30 minutes post-drug. Data from eight animals/group are presented as mean ± SEM.

Figure 5

Figure 5

Effect of lacosamide and morphine on mechanical hyperalgesia after monosodium iodoacetate (MIA) injection. Effect of lacosamide and morphine on paw withdrawal threshold in the paw pressure test in MIA-treated animals on (a) day 3, (b) day 7 and (c) day 14 after arthritis induction. Rats were tested 45 to 60 minutes post-drug. Data from 12 animals/group are presented as mean ± SEM. *P < 0.05 Dunnett's test versus MIA/vehicle treated animals.

Figure 6

Figure 6

Effect of diclofenac on mechanical hyperalgesia after monosodium iodoacetate (MIA) injection. Effect of diclofenac on paw withdrawal threshold in the paw pressure test in MIA-treated animals on days 3, 7 and 14 after arthritis induction. Rats were tested 45 to 60 minutes post-drug. Data from 12 animals/group are presented as mean ± SEM. *P < 0.05 Dunnett's test versus MIA/vehicle treated animals.

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