Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.
Bottom Line: To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed.These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8.Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs).
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.Show MeSH
Related in: MedlinePlus
Mentions: Expression analysis revealed that TRPM8 and TRPA1 channels were minimally affected, although TRPA1 was found to be slightly increased. In addition to its role in detecting irritant chemicals, TRPA1 has been controversially implicated in noxious cold and mechanical sensation; therefore, we used the selective TRPA1 antagonist HC-030031 to evaluate its effects on oxaliplatin-induced neuropathy. As presented in Fig 6A, oxaliplatin-mediated cold hyperalgesic animals were treated intraperitoneal (i.p.) with HC030031 at 100 mg/kg (an in vivo active concentration in rodents (Eid et al, 2008)) or its vehicle. Thirty minutes after treatment, mice were subjected to the cold tolerance test. HC-030031 treatment had no effect on the oxaliplatin-induced cold hyperalgesia. Interestingly, in vehicle-treated animals that show intolerance to noxious cold at much colder values (∼5°C), HC030031 attenuated the nocifencive behaviour of the mice. In contrast, the mechanical hyperalgesia was completely corrected by HC030031 (Fig 6B), corroborating the notion that TRPA1 channels play an important role in the mechanisms responsible for mechanical hypersensitivity in neuropathic condition (Eid et al, 2008). However, acute mechanical pain perception in control animals was not affected by the TRPA1 antagonist suggesting that the transduction of mechanical stimuli is governed by multiple molecular substrates.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.