Establishment of a novel objective and quantitative method to assess pain-related behavior in monosodium iodoacetate-induced osteoarthritis in rat knee.
BACKGROUND
Pain in osteoarthritis (OA) patients can be present at rest but typically worsens with movement of the affected joint. However, useful assessment methods of movement-induced pain in animal models are limited. Here, we describe the reduction of spontaneous activity in a rat model of OA as an objective and quantifiable behavioral pain that can predict the analgesic activity of a variety of agents following single-dose administration.


METHODS
OA was induced in male Sprague-Dawley (SD) rats by intra-articular injection of monoiodoacetate (MIA), and the joint degeneration was assessed with histologic and radiographic analyses. Spontaneous activities were measured in nonhabituated rats using standard, photocell-based monitor systems in the dark. To investigate the potential of the OA model to predict analgesic activity, a number of nonsteroidal anti-inflammatory drugs (NSAIDs) and atypical analgesic drugs were used.


RESULTS
Biphasic reduction of total distance and number of rears was observed during the course of experiment after administering 1mg and 0.3mg of MIA, respectively. We found that number of rears was the most sensitive to MIA-induce OA and displayed the greatest percentage decrease in activity. Joint degeneration was observed with decreased bone mineral density and loss of articular cartilage 28days post-MIA injection. Appropriate dosage of opioids reversed MIA-induced decrease of number of rears indicating that reduction of this vertical spontaneous activity reflects pain-associated behavior. As high-doses of opioids reduced spontaneous activity, the sedative effect can be distinguished from the analgesic effect. Analgesic treatment indicates the coexistence of an inflammatory pain state (early phase) sensitive to NSAIDs and a non-inflammatory pain state (late phase) resistant to NSAID treatment.


CONCLUSIONS
This study indicates that unlike standard measures of analgesia such as alteration in thermal or mechanical sensitivity, measurement of spontaneous activity is a validated method for measuring the effects of analgesics in rats with OA knee joints. Moreover, the animals require no habituation, and thus behavioral observation subjectivity is eliminated.
Biological Research Laboratories III, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Hiroyuki
H
Nagase
Seiichiro
S
Kumakura
Kohei
K
Shimada
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015519:Bone Density; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007461:Iodoacetates / Q000008:administration & dosage / Q000633:toxicity; D007719:Knee Joint / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007461:Iodoacetates