Circadian pattern of spontaneous behavior in monarthritic rats- A novel global approach to evaluation of chronic pain and treatment effectiveness-

M. Millecamps, D. Jourdan, S. Leger, M. Etienne, A. Eschalier et al.

Faculty of Medicine, Medical Laboratory of Pharmacology, Clermont-Ferrand, France.

Arthritis & Rheumatism

Objective: Preclinical evaluation is an essential step in the assessment of new antiinflammatory or analgesic drugs. This study was undertaken to develop a new mode of evaluation of drug effectiveness based on behavior indicating well-being in a rat model of chronic inflammatory pain. We chose to examine the circadian pattern of spontaneous behavior. Methods: The work was performed with a model of chronic monarthritis induced by Freund's complete adjuvant. Variations in behavioral patterns during the time course of arthritis were analyzed. In a second phase, the impact of acetaminophen and 2 nonsteroidal antiinflammatory drugs (aspirin and celecoxib), which are currently used in clinical practice to treat chronic inflammation, was studied after 7 days of treatment. Results: The nocturnal pattern of activity of healthy rats comprised 3 main bursts. Chronic painful monarthritis altered this spontaneous pattern of nocturnal behavior (normal period of activity). Monarthritic rats showed a decrease in the total time spent in activity during the night, and lost their pattern of activity. These behavioral disturbances were reversed after long-term treatment with acetaminophen or celecoxib, with celecoxib appearing to be more effective. Aspirin was ineffective. Conclusion: These results enabled us to test this new procedure as a means of assessing well-being or ill- being during stages of chronic inflammatory pain in rats, and the effectiveness of repeated pharmacologic treatments. Arthritis and other rheumatic conditions are among the most common chronic diseases: they affected 70 million US adults in 2001, and are the major cause of disability among US adults (60% of US population older than 65 years). These conditions are characterized by persistent inflammatory pain, which is treated with nonsteroidal antiinflammatory drugs or corticosteroids. However, long-term use of these drugs induces numerous gastrointestinal side effects, and their real impact on patient quality of life remains uncertain. The search for new pharmacologic treatments for these conditions continues, but preclinical evaluation of their effectiveness has lagged behind. The predictive ability of current techniques used to assess drug effectiveness remains approximate because they are based on reflex or pseudo-affective reactions to acute or subacute painful stimuli in animals, which have limited relevance to predictability in humans. Investigators have attempted to identify specific behaviors as markers of discomfort generated by pain (paw position, weight load on each leg, gait analysis, or locomotion). However, there is only putative evidence that they may be of use in pharmacologic studies since they adopt a functional approach to disease rather than constituting a real evaluation of spontaneous pain. Many clinical studies on pain are based on general questionnaires given directly to the patients in pain. Assessment of patient quality of life is becoming more common and generally includes evaluation of pain, quality of sleep, social life, cognitive and emotional status, mobility or walking, and normal work and daily home activities. One of the main results of pain is deterioration in activity patterns (loss of sleep, diurnal somnolence, loss of a general day-to-day rhythm, altered social life). As a followup to these clinical observations made while patients are in a state of chronic pain, we thought it would be useful to evaluate the impact of chronic pain on patterns of activity in rats, and to assess whether the resulting modifications could be used in pharmacologic studies as a marker of spontaneous pain. The aim of this study was to develop a new mode of evaluation of drug effectiveness based on well-being behaviors in freely moving rats in chronic inflammatory pain. We first examined the circadian patterns of the spontaneous activities in monarthritic rats. We then studied the impact of a 7-day treatment with acetaminophen, aspirin, and celecoxib on spontaneous behavior, mechanical allodynia, and inflammation.

BIOSEB Instruments Used:
Von Frey Filaments (Bio-VF-M)

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