Clinical grade bortezomib (Velcade®) 3.5mg/vial (Millennium Pharmaceuticals, Inc) was diluted with 0.9% sterile saline (Fresenius Kabi, UK) to prepare a 0.2mg/ml bortezomib solution. For vehicle administration, a solution of 0.2mg/ml D-mannitol (Sigma, UK) in 0.9% sterile saline was used to replicate Velcade® vehicle solution. Animals received 0.2mg/kg bortezomib, or an equivalent volume of vehicle solution, intraperitoneally on day 0, 3, 7 and 10 [16 (link)].
Three key time-points were investigated in these models of CIPN. Day 4 (bortezomib) or day 7 (paclitaxel and oxaliplatin), prior to the onset of pain-like behaviour; peak pain, when animals reached the peak of mechanical hypersensitivity (paclitaxel: day 28–31; oxaliplatin: day 27–29; bortezomib: day 23–25); and resolution of chemotherapy-induced pain behaviour, when animals returned to their individual baseline response on two consecutive occasions (paclitaxel day 174; oxaliplatin day 147–148; bortezomib day 116–124). The peak pain and resolution of pain time-points within a cohort occurred on more than one day, as they differed between rats and were dependent on individual rat behaviour compared to its baseline. Raw behavioural data for all animals is shown in S1 Raw data.
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