Figure 1: Cold hypersensitivity over time in oxaliplatin-treated macaques. To assess changes to temperature sensitivity, the tail withdrawal test was used [43]. Following habituation to chair restraint, baseline responses of awake cynomolgus macaques to 10°C cold water were measured. The distal 10 cm of the tail was cleaned and immersed in a cold water bath. The amount of time (in seconds) between tail immersion and withdrawal from the water was recorded and reported as the withdrawal latency. A maximum immersion time of 20 sec. was utilized. Prior to oxaliplatin treatment, the withdrawal latency to cold water was 20 sec. (a) Significant sensitivity to cold (10°C) was observed following oxaliplatin treatment. Following baseline assessment, macaques were treated with oxaliplatin (i.v. 5 mg/kg, 2 hr. infusion; ▲). Three days after oxaliplatin treatment (↓), the mean withdrawal latency was significantly decreased compared to the pretreatment latency, indicating cold hypersensitivity. Hypersensitivity to cold dissipated over time—by seven days after oxaliplatin treatment, the response to cold was similar to that prior to oxaliplatin treatment. Subsequent oxaliplatin treatments evoked an acute hypersensitivity to cold beginning three days after treatment. By contrast, vehicle treatment (i.v. glucose 5% in water; ◯) did not significantly affect response to cold. Data presented as mean ± S.E.M. Vehicle, . Oxaliplatin, . , versus baseline (day “0”). (b) Pharmacological modulation of oxaliplatin-induced neuropathic pain in macaques. Tail withdrawal latencies were measured three days after oxaliplatin treatment. Macaques were tested one hour after treatment (one and two hours after tramadol treatment) [43]. The antidepressant drug duloxetine (p.o. 30 mg/kg) reversed hypersensitivity to cold. By contrast, the anticonvulsant drug pregabalin (p.o. 30 mg/kg) and the opioid/serotonin-norepinephrine reuptake inhibitor tramadol (p.o. 30 mg/kg) did not. Data presented as mean ± S.E.M. /duloxetine, /pregabalin, /tramadol. versus pretreatment (“Pre”), paired t-test. Slightly modified from [43].