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.

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

“…214,229 In theory, an NHP-model might be an improvement over widely used rodent models, but the use of NHPs has been challenged on ethical and scientific grounds. 230 A viable and rapidly developing approach is to use a model that avoids the use of non-human tissues and which instead incorporates sensory neurons derived from human stem cells.…”

Duloxetine Attenuates Paclitaxel-Induced Peripheral Nerve Injury by Inhibiting p53-Related Pathways

“…There were three duloxetine treatment groups with different doses of duloxetine: 10 mg/kg [P+D (L)], 20 mg/kg [P+D (M)] and 30 mg/kg [P+D (H)] (Toyama et al, 2017;Shidahara et al, 2016). Duloxetine was injected i.p.…”

Gaps in Understanding Mechanism and Lack of Treatments: Potential Use of a Nonhuman Primate Model of Oxaliplatin-Induced Neuropathic Pain

“…Oxaliplatin treatment in cynomolgus macaques leads to a significant hypersensitivity to 10°C cold, beginning three days after intravenous oxaliplatin infusion (two-hour i.v. infusion 5 mg/kg; human equivalent dose of 1.6 mg/kg [ 13 , 43 ]) ( Figure 1 ). Furthermore, treatment with the serotonergic-norepinephrine reuptake inhibitor duloxetine (p.o.…”

“…30 mg/kg) did not alter cold hypersensitivity ( Figure 1 ). The lack of efficacy of pregabalin and tramadol in the macaque model contrasts with robust efficacy observed in rodent models of oxaliplatin-induced neuropathic pain [ 33 , 43 – 45 ]. The limited macaque pharmacological data parallel findings from randomized, placebo-controlled clinical trials, in that duloxetine showed significant efficacy in chemotherapy-induced peripheral neuropathic pain [ 46 ], whereas pregabalin did not [ 47 ].…”