title: Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin-induced neuropathic cold hypersensitivity.
abstract: Oxaliplatin is a first-line treatment for colorectal cancer. However, shortly following treatment, cold-evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin-induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy-induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water ("cold hypersensitivity") was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin-induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin-treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin-induced peripheral neuropathy.
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Shidahara
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nemoto
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Awaga
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takashima
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Aldric
authors.initials: A
authors.lastname: Hama
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
keywords: Chemotherapy‐induced peripheral neuropathy; Macaca fascicularis; cold hypersensitivity; duloxetine; preclinical translation; pregabalin; tramadol