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Efficacy of CR4056, a First-In-Class imidazoline-2 Analgesic Drug, in Comparison With Naproxen in Two Rat Models of Osteoarthritis

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Efficacy of CR4056, a First-In-Class imidazoline-2 Analgesic Drug, in Comparison With Naproxen in Two Rat Models of Osteoarthritis

Eleonora Comi et al. J Pain Res.

Abstract

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 7 days 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: CR4056; MIA; MMT; imidazoline-2 receptors; osteoarthritis; pain.

Conflict of interest statement

Disclosure This manuscript has not been published and is not under consideration for publication elsewhere. Rottapharm Biotech as a corporate entity had no role in the conduct of the study, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. Eleonora Comi is a PhD student with no competing interests. Valeria Mauri is a postgraduate student with no competing interests. All the other authors are employees of Rottapharm Biotech and report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
MIA model of OA pain: effect of CR4056 and naproxen on mechanical allodynia. Rats were injected with 1 mg/50 μl of MIA or saline (sham group) in the right knee. Mechanical withdrawal threshold (in grams) was evaluated in the ipsilateral paw by von Frey test, using a Dynamic Plantar Aesthesiometer, prior and 7, 14, and 21 days after MIA injection. CR4056 (2 and 6 mg/kg) and naproxen (10 mg/kg) were administered orally, once a day under the schedule indicated by the arrows positioned in the graph below the axis of time (days). Data, collected 90 minutes after the drug administration, represent the mean±SEM of six animals per group. Notes: aP=0.007, bP=0.031, cP=0.001, dP=0.003 versus MIA group treated with vehicle; two-way mixed model ANOVA, Holm-Sidak test. Abbreviations: MIA, monoiodoacetate; OA, osteoarthritis; ANOVA, one-way analysis of variance, SEM, standard error of the mean.
Figure 2
Figure 2
MIA model of OA pain: effect of CR4056 and naproxen on mechanical hyperalgesia. Rats were injected with 1 mg/50 μl of MIA or saline (sham group) in the right knee. Mechanical withdrawal threshold (in grams) was evaluated in the ipsilateral knee using a Pressure Application Measurement (PAM) device, prior and 7, 14, and 21 days after MIA injection. CR4056 (2 and 6 mg/kg) and naproxen (10 mg/kg) were administered orally, once a day under the schedule indicated by the arrows positioned in the graph below the axis of time (days). Data, collected 90 minutes after the drug administration, represent the mean±SEM of six animals per group. Notes: aP<0.001, bP<0.001, cP<0.001, dP=0.001 versus MIA group treated with vehicle; two-way mixed model ANOVA, Holm-Sidak test. Abbreviations: MIA, monoiodoacetate; OA, osteoarthritis; ANOVA, one-way analysis of variance, SEM, standard error of the mean.
Figure 3
Figure 3
MMT model of OA: effect of CR4056 and naproxen on the behavioral assessment of hind paw weight distribution (HPWD). (A) The difference in HPWD (Δ) between contralateral and ipsilateral knees (in grams) was evaluated 1 day before and 14, 28, 35, and 42 days after MMT surgery using an incapacitance tester. CR4056 (6 mg/kg) and naproxen (10 mg/kg) were administered orally, once a day under the schedule indicated by the arrows positioned in the graph below the axis of time (days). Data, collected 24 hours after the drug administration, represent the mean ± SEM of nine animals per group. aP<0.001 versus MMT control rats treated with vehicle; two-way mixed model ANOVA, Holm-Sidak test. (B) Efficacy of 2 weeks of treatment with CR4056 (6 mg/kg) and naproxen (10 mg/kg) assessed as percent difference between Δ weight measured at day 28 (before the beginning of treatments) and day 42 after MMT surgery. Data (N=9 animals/group) were plotted as box-and-whisker plot. The box spans the interquartile range (25th–75th percentiles), while the line within the box denotes the median. Whiskers extend from the 10th to the 90th percentiles. Statistical significance was calculated by one-way ANOVA followed by Tukey’s multiple comparisons test. Abbreviations: MMT, medial meniscal tear; OA, osteoarthritis; ANOVA, one-way analysis of variance, SEM, standard error of the mean; ns, not significant.

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