Though advances in cancer detection and therapy have significantly advanced life expectancy in cancer patients, quality of life may be severely compromised due to the development of painful neuropathy [
1‐
4]. Chemotherapy-induced peripheral neuropathy is a common, rapidly induced effect observed soon after administration of anti-cancer agents [
5‐
7] resulting in numbness, tingling and pain distributed in a distal stocking-and-glove pattern [
8,
9]. Oxaliplatin is a highly active antineoplastic agent, licensed for treating colorectal cancer, that contains a platinum complex with a 1,2-diaminocyclohexane (DACH) carrier ligand designed to overcome resistance to other antineoplastic agents [
10]. The volume of distribution of platinum is high, due to the lipophilicity of oxaliplatin metabolites, which bind irreversibly to proteins, DNA and other cellular molecules. The terminal half-life of oxaliplatin is long, and neurotoxicity is very common in patients treated with this drug, with 68% experiencing some degree of toxicity. The dose-limiting toxicity is exacerbated by exposure to cold [
11‐
14] at doses of or greater than 135 mg/m
2, with early development of allodynia and hypersensitivity to heat and cold stimuli [
15].
Since thermal hypersensitivity is a significant early consequence of oxaliplatin treatment, we investigated the involvement of the ion channels expressed by nociceptors involved in thermosensation. These plasma membrane bound ion channels belong to the transient receptor potential (TRP), superfamily of receptors [
18]. TRPV1 (vanilloid subtype 1), is activated by noxious heat (>43°C) [
19] capsaicin, low pH, the inflammatory mediators arachidonic acid [
20] and bradykinin [
21] leading to the perception of pain, and thermal hypersensitivity [
22]. The sensitivity and expression of TRPV1 is modulated by the neurotrophins nerve growth factor (NGF) [
23‐
25] and glial cell-line derived neurotrophic factor (GDNF) in rodents [
26] and humans [
27]. The levels of NGF, GDNF and its receptor ret are increased in injured human peripheral nerves and ganglia [
28,
29] and in tissues with chronic inflammation [
30‐
32]. TRPV1 expression is upregulated in conditions of chronic pain [
33‐
35] for which it is an important target. As oxaliplatin treated individuals report hypersensitivity to cold stimuli during or soon after infusion, we examined the functional effects of acute oxaliplatin treatment on TRPM8 and TRPA1, two ion channels involved in cool and noxious cold perception respectively. TRPA1 is activated by temperatures less than 17°C, the chemicals mustard oil and cinnamaldehyde (CA), and the cooling agents icilin and menthol; it is expressed in nociceptors, and involved in pain perception although there is inconsistent evidence for its role in cold detection [
36‐
42]. TRPA1 is colocalized with 30% - 50% TRPV1 expressing neurons in rodent [
43] and human DRG, where the expression of both channels is increased after injury [
44]. Like TRPV1, the responses of TRPA1 to CA demonstrate tachyphylaxis, and are enhanced in the presence of NGF, GDNF (also upregulated in conditions of chronic pain), and NT3 [
44]. TRPM8 (subtype melastatin 8), is expressed in a distinct subset of nociceptors, and activated by cool temperature (<25°C), menthol, icilin [
45,
46], and the carboxyamide derivative WS-12 [
47]. Here, we describe the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons.