Efficacy of CR4056, a first-in-class imidazoline-2 analgesic drug, in comparison with naproxen in two rat models of osteoarthritis

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:

• osteoarthritis
• pain
• CR4056
• imidazoline-2 receptors
• MIA
• MMT

Supplementary materials

Figure S1 Determination of allodynia in the MMT model of OA via manual von Frey analysis. Allodynia was measured via von Frey filaments in SD rats in which OA has been induced by MMT. Even if there is a trend toward a higher sensitivity (i.e. lower withdrawal threshold in operated animals versus sham), this difference did not reach a statistical significance. Moreover, the narrow difference induced by OA does not allow placing a dose-response curve for an analgesic compound such as CR4056. Data are presented as mean ± SEM.

Abbreviations: MMT, medial meniscal tear; OA, osteoarthritis; SD, Sprague Dawley.

Figure S2 Determination of HPWD in the MIA model of OA in Wistar rats: effect of 20 mg/kg CR4056. HPWD has been evaluated as described. It is possible to observe the higher variability of HPWD (i.e. basal groups) compared to the MMT model. Nevertheless, also in this paradigm, CR4056 administration (20 mg/kg; oral, QD) induced a statistically significant reduction versus vehicle-treated animals. On the contrary, no effect is observed with naproxen (10 mg/kg; oral, QD). Data are presented as mean ± SEM; *P<0.05.

Abbreviations: HPWD, hind paw weight distribution; MIA, monoiodoacetate; OA, osteoarthritis; SEM; standard error of the mean.

Table S1 Statistical analysis of HPWD in the MMT model of OA

Table S2 Statistical analysis of HPWD in the MIA model of OA

Acknowledgments

The authors wish to thank Dr. Albino Bonazzi for his institutional reporting and useful discussion on this project, Dr. Paolo Garofalo for his help in statistical analysis, Mr. Luca Catapano and Mr. Dario Tremolada for their skilful technical help in settling the experimental conditions, and Mrs. Laura Radaelli for secretarial assistance. Preliminary results of this study were presented at the 2015 World Congress on Osteoarthritis (OARSI), held in Seattle, WA, USA (Caselli et al, Osteoarthritis Cartilage, 2015), at the Fifth International Congress on Neuropathic Pain (NeuPSIG) held in Nice, France (Comi et al, 2015), and at the 2016 World Congress on Osteoarthritis (OARSI), held in Amsterdam, the Netherlands (Comi et al, Osteoarthritis Cartilage, 2016). This study was funded by Rottapharm Biotech.

Author contributions

All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

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.