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Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.

Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E - EMBO Mol Med (2011)

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).

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

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Schematic representation of oxaliplatin-mediated changes in cold and mechanically sensitive primary afferent fibres (adapted from (Madrid et al, 2009))Monomodal cold-specific fibres use TRPM8 as the main detector of innocuous cool and noxious cold stimuli. Oxaliplatin modifies their excitability by decreasing inhibitory potassium channels and increasing excitatory channels with a prominent effect on HCN1.Polymodal cold and mechanosensitive fibres affected by oxaliplatin also use TRPM8 as cold detector in addition to yet to be identified excitatory mechanosensors. Distinct from cold specific fibres, HCN channels are not present in these neurons reflecting the lack of ivabradine effect in mechanical pain and the incomplete reversal of cold tolerance.Mechanosensitive fibres with up-regulated TRPA1 and down-regulated K2P in their mechanosensory machinery convey oxaliplatin-mediated mechanical hypersensitivity.
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fig10: Schematic representation of oxaliplatin-mediated changes in cold and mechanically sensitive primary afferent fibres (adapted from (Madrid et al, 2009))Monomodal cold-specific fibres use TRPM8 as the main detector of innocuous cool and noxious cold stimuli. Oxaliplatin modifies their excitability by decreasing inhibitory potassium channels and increasing excitatory channels with a prominent effect on HCN1.Polymodal cold and mechanosensitive fibres affected by oxaliplatin also use TRPM8 as cold detector in addition to yet to be identified excitatory mechanosensors. Distinct from cold specific fibres, HCN channels are not present in these neurons reflecting the lack of ivabradine effect in mechanical pain and the incomplete reversal of cold tolerance.Mechanosensitive fibres with up-regulated TRPA1 and down-regulated K2P in their mechanosensory machinery convey oxaliplatin-mediated mechanical hypersensitivity.

Mentions: Collectively, our results demonstrate that oxaliplatin induces peripheral neuropathy in mice with a clear exacerbation of cold detection and development of mechanical hyperalgesia. Cold-sensitive sensory fibres expressing TRPM8 and mechano-sensitive fibres expressing TRPA1 are potently affected by this toxic chemotherapy side effect. We found that within these neurons, oxaliplatin alters ion channel gene expression in agreement with transcriptional effects reported on cancer cell lines. The potassium channels TREK1, TRAAK, and, to a lesser extent, KV1.1 are repressed while TRPA1, NaV1.8, and HCN1 channels are transcriptionally up-regulated in these particular subclasses of sensory fibres as illustrated in Fig 10. The translational consequences of these findings for patients would be that pharmacological activators of the repressed potassium channels or antagonists of the up-regulated channels are potential tailored preventive treatments of the painful side effects of oxaliplatin. The availability of such molecules like ivabradine currently used in clinic could be of interest, especially as effective drugs for prevention are few and do not exist for curative care (Wolf et al, 2008). Further development of even more specific ligands for the identified channels is pivotal in future treatment of chemotherapy-induced neuropathies.


Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.

Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E - EMBO Mol Med (2011)

Schematic representation of oxaliplatin-mediated changes in cold and mechanically sensitive primary afferent fibres (adapted from (Madrid et al, 2009))Monomodal cold-specific fibres use TRPM8 as the main detector of innocuous cool and noxious cold stimuli. Oxaliplatin modifies their excitability by decreasing inhibitory potassium channels and increasing excitatory channels with a prominent effect on HCN1.Polymodal cold and mechanosensitive fibres affected by oxaliplatin also use TRPM8 as cold detector in addition to yet to be identified excitatory mechanosensors. Distinct from cold specific fibres, HCN channels are not present in these neurons reflecting the lack of ivabradine effect in mechanical pain and the incomplete reversal of cold tolerance.Mechanosensitive fibres with up-regulated TRPA1 and down-regulated K2P in their mechanosensory machinery convey oxaliplatin-mediated mechanical hypersensitivity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3377073&req=5

fig10: Schematic representation of oxaliplatin-mediated changes in cold and mechanically sensitive primary afferent fibres (adapted from (Madrid et al, 2009))Monomodal cold-specific fibres use TRPM8 as the main detector of innocuous cool and noxious cold stimuli. Oxaliplatin modifies their excitability by decreasing inhibitory potassium channels and increasing excitatory channels with a prominent effect on HCN1.Polymodal cold and mechanosensitive fibres affected by oxaliplatin also use TRPM8 as cold detector in addition to yet to be identified excitatory mechanosensors. Distinct from cold specific fibres, HCN channels are not present in these neurons reflecting the lack of ivabradine effect in mechanical pain and the incomplete reversal of cold tolerance.Mechanosensitive fibres with up-regulated TRPA1 and down-regulated K2P in their mechanosensory machinery convey oxaliplatin-mediated mechanical hypersensitivity.
Mentions: Collectively, our results demonstrate that oxaliplatin induces peripheral neuropathy in mice with a clear exacerbation of cold detection and development of mechanical hyperalgesia. Cold-sensitive sensory fibres expressing TRPM8 and mechano-sensitive fibres expressing TRPA1 are potently affected by this toxic chemotherapy side effect. We found that within these neurons, oxaliplatin alters ion channel gene expression in agreement with transcriptional effects reported on cancer cell lines. The potassium channels TREK1, TRAAK, and, to a lesser extent, KV1.1 are repressed while TRPA1, NaV1.8, and HCN1 channels are transcriptionally up-regulated in these particular subclasses of sensory fibres as illustrated in Fig 10. The translational consequences of these findings for patients would be that pharmacological activators of the repressed potassium channels or antagonists of the up-regulated channels are potential tailored preventive treatments of the painful side effects of oxaliplatin. The availability of such molecules like ivabradine currently used in clinic could be of interest, especially as effective drugs for prevention are few and do not exist for curative care (Wolf et al, 2008). Further development of even more specific ligands for the identified channels is pivotal in future treatment of chemotherapy-induced neuropathies.

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).

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

Show MeSH
Related in: MedlinePlus