Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons

Background: Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests as tingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy. Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing reveals cold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons. Results: 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 mu g/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 +/- 13 a.u., n = 3, P < 0.05), compared to controls (120.3 +/- 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 mu g/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 +/- 0.6% without oxaliplatin, to 171.26 +/- 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 +/- 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 +/- 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 +/- 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 +/- 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected. Conclusions: Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin.