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Eleonora Comi,1,2 Marco Lanza,1 Flora Ferrari,1 Valeria Mauri,1,3 Gianfranco Caselli,1 Lucio Claudio Rovati1 1Department of Pharmacology and Toxicology, Rottapharm Biotech, 2PhD Program in Neuroscience, University of Milan-Bicocca, 3Department of Surgery and Translational Medicine, University ofMilan-Bicocca, Monza,Italy Purpose: CR4056, (2-phenyl-6-(1H-imidazol-1yl) quinazoline), an imidazoline-2 (I2) receptor ligand, is a promising analgesic drug that has been reported to be effective in several animal models of pain. The aim of this study was to evaluate the effects of CR4056 in two well-established rat models of osteoarthritis (OA), mimicking the painful and structural components of human OA.Methods: Knee OA was induced either by single intra-articular injection of monoiodoacetate (MIA) or by medial meniscal tear (MMT) in the right knee of male rats. In the MIA model, allodynia and hyperalgesia were measured as paw withdrawal threshold to mechanical stimulation. In the MMT model, pain behavior was analyzed as weight-bearing asymmetry (i.e. difference in hind paw weight distribution, HPWD) between the injured and the contralateral limbs.Results: Acute oral administration of CR4056, 14 days after MIA injection, significantly and dose-dependently reduced allodynia and hyperalgesia 90 minutes after treatment, whereas acute naproxen administration significantly reduced allodynia but not hyperalgesia. After 7days of repeated treatment, both CR4056 and naproxen showed significant anti-allodynic and anti-hyperalgesic effects in the MIA model. Rats undergoing MMT surgery developed a significant and progressive asymmetry in HPWD compared with sham-operated animals. Repeated treatment with CR4056 significantly reduced the progression of the pain behavior, whereas naproxen had no effects.Conclusion: The data presented here show that the I2 ligand CR4056 could be a new effective treatment for OA pain. The compound is currently under Phase II clinical evaluation for this indication. Keywords: osteoarthritis, pain, CR4056, imidazoline-2 receptors, MIA, MMT

Purpose: Joint pain is the cardinal symptom of OA although it poorly correlates with OA joint structure changes. Interestingly, OA pain is driven by both nociceptive and neuropathic mechanisms. The analgesic efficacy of CR4056, an I2 receptor ligand currently in phase II clinical trials, was previously reported in the OA pain model obtained by the intra-articular injection of monosodium iodoacetate (MIA) in the rat knee. Moreover, CR4056 evidenced a remarkable analgesic activity in several animal models of inflammatory, neuropathic and postoperative pain. The aim of this study was to evaluate the effect of CR4056 in a well-established model of surgically-induced OA able to mimic the structural and painful components of human OA. Methods: OA was induced in male Sprague Dawley rats (335-370 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial right joint (MMT model). Hind paw weight bearing distribution was assessed as indirect measure of spontaneous pain by using an incapacitance tester (2Biological Instruments Snc, Besozzo, Italy), prior to surgery and 14, 28, 35 and 42 days post-surgery. Control rats were subjected to sham surgery, while treatments after MMT consisted of 6 mg/kg CR4056, or 10 mg/kg naproxen as an active control, or vehicle (9 animals/group) and they were administered orally as subacute treatment from 28 to 42 days after surgery. Statistical analysis was performed by Two-way RM ANOVA, followed by Tukey's multiple comparisons test. Results: MMT surgery resulted in a significant development of right-left hind paw weight bearing imbalance at each experimental time point, compared with the sham group (data expressed as difference of weight bearing between contralateral and ipsilateral paw). The difference in weight bearing distribution between sham and MMT rats gradually increased throughout the study, reaching its peak 42 days post-surgery in animals receiving vehicle (mean ± sem, 0.83 ± 1.87 vs. 65.92 ± 2.26, respectively). Subacute oral administration of 6 mg/kg CR4056 for 2-weeks from 28 to 42 days after surgery induced a significant reduction of right-left hind paw weight bearing imbalance, compared with the MMT control group treated with vehicle (42 days post-surgery mean ± sem, 39.84 ± 3.47 vs. 65.92 ± 2.26, respectively), as illustrated in the Figure. Conversely, 10 mg/kg naproxen was devoid of noticeable effect on weight bearing imbalance after 2-weeks subacute treatment. Conclusions: The data presented here further evidence that the imidazoline I2 receptor ligand CR4056 could represent a new highly effective analgesic treatment option for OA pain.