CR4056, a new analgesic I2 ligand, is highly effective against bortezomib-induced painful neuropathy in rats

Cristina Meregalli,¹ Cecilia Ceresa,¹ Annalisa Canta,¹ Valentina Alda Carozzi,¹ Alessia Chiorazzi,¹ Barbara Sala,¹ Norberto Oggioni,¹ Marco Lanza,² Ornella Letar,i² Flora Ferrari,² Federica Avezza,¹ Paola Marmiroli,¹ GianFranco Caselli,² Guido Cavaletti<sup>1

1</sup>Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, ²Pharmacology and Toxicology Department, Rottapharm | Madaus Research Center, Monza, Italy

Abstract: Although bortezomib (BTZ) is the frontline treatment for multiple myeloma, its clinical use is limited by the occurrence of painful peripheral neuropathy, whose treatment is still an unmet clinical need. Previous studies have shown chronic BTZ administration (0.20 mg/kg intravenously three times a week for 8 weeks) to female Wistar rats induced a peripheral neuropathy similar to that observed in humans. In this animal model of BTZ-induced neurotoxicity, the present authors evaluated the efficacy of CR4056, a novel I2 ligand endowed with a remarkable efficacy in several animal pain models. CR4056 was administered in a wide range of doses (0.6–60 mg/kg by gavage every day for 2–3 weeks) in comparison with buprenorphine (Bupre) (28.8 µg/kg subcutaneously every day for 2 weeks) and gabapentin (Gaba) (100 mg/kg by gavage every day for 3 weeks). Chronic administration of BTZ reduced nerve conduction velocity and induced allodynia. CR4056, Bupre, or Gaba did not affect the impaired nerve conduction velocity. Conversely, CR4056 dose-dependently reversed BTZ-induced allodynia (minimum effective dose 0.6 mg/kg). The optimal dose found, 6 mg/kg, provided a constant pain relief throughout the treatment period and without rebound after suspension, being effective when coadministered with BTZ, starting before or after allodynia was established, or when administered alone after BTZ cessation. A certain degree of tolerance was seen after 7 days of administration, but only at the highest doses (20 and 60 mg/kg). Bupre was effective only acutely, since tolerance was evident from the fourth day onwards. Gaba showed a significant activity only at the fourth day of treatment. CR4056, over the range of concentrations of 3–30 µM, was unable to hinder BTZ cytotoxicity on several tumor cell lines, which could indicate that this substance does not directly interfere with BTZ antitumor activity. Therefore, CR4056 could represent a new treatment option for BTZ-induced neuropathic pain.

Keywords: imidazoline I2 receptor ligand, antinociception, allodynia, neuropathic pain, bortezomib