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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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Related in: MedlinePlus

The TRPA1 channel blocker HC030031 does not affect oxaliplatin mediated cold hypersensitivity but reverses mechanical hyperalgesiaFilled black circles and bars represent the basal values before oxalipatin injection, while the open circles and bars corresponds to the oxaliplatin (6 mg/kg) treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or vehicle. The red circles/bars and the blue circles/bars represent, respectively, the oxaliplatin–vehicle and the oxaliplatin–HC030031 groups (n = 10 per group). Filled black triangle and grey bars represent the basal values before vehicle injection, while the black open triangle and hatched bars corresponds to the vehicle treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or its vehicle. The red triangle/hatched bars and the blue triangles/hatched bars represent, respectively, the vehicle–vehicle and the vehicle–HC030031 groups (n = 10 per group).Lack of effect of TRPA1 channel blockade with acute HC030031 treatment on oxaliplatin cold hyperalgesia (left panel). The same treatment reduces normal cold tolerance in control mice (right panel).Reversal of oxaliplatin-mediated mechanical hyperalgesia by HC030031 in similar experimental conditions as in (A) (n = 20 or 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
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fig06: The TRPA1 channel blocker HC030031 does not affect oxaliplatin mediated cold hypersensitivity but reverses mechanical hyperalgesiaFilled black circles and bars represent the basal values before oxalipatin injection, while the open circles and bars corresponds to the oxaliplatin (6 mg/kg) treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or vehicle. The red circles/bars and the blue circles/bars represent, respectively, the oxaliplatin–vehicle and the oxaliplatin–HC030031 groups (n = 10 per group). Filled black triangle and grey bars represent the basal values before vehicle injection, while the black open triangle and hatched bars corresponds to the vehicle treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or its vehicle. The red triangle/hatched bars and the blue triangles/hatched bars represent, respectively, the vehicle–vehicle and the vehicle–HC030031 groups (n = 10 per group).Lack of effect of TRPA1 channel blockade with acute HC030031 treatment on oxaliplatin cold hyperalgesia (left panel). The same treatment reduces normal cold tolerance in control mice (right panel).Reversal of oxaliplatin-mediated mechanical hyperalgesia by HC030031 in similar experimental conditions as in (A) (n = 20 or 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.

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.


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)

The TRPA1 channel blocker HC030031 does not affect oxaliplatin mediated cold hypersensitivity but reverses mechanical hyperalgesiaFilled black circles and bars represent the basal values before oxalipatin injection, while the open circles and bars corresponds to the oxaliplatin (6 mg/kg) treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or vehicle. The red circles/bars and the blue circles/bars represent, respectively, the oxaliplatin–vehicle and the oxaliplatin–HC030031 groups (n = 10 per group). Filled black triangle and grey bars represent the basal values before vehicle injection, while the black open triangle and hatched bars corresponds to the vehicle treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or its vehicle. The red triangle/hatched bars and the blue triangles/hatched bars represent, respectively, the vehicle–vehicle and the vehicle–HC030031 groups (n = 10 per group).Lack of effect of TRPA1 channel blockade with acute HC030031 treatment on oxaliplatin cold hyperalgesia (left panel). The same treatment reduces normal cold tolerance in control mice (right panel).Reversal of oxaliplatin-mediated mechanical hyperalgesia by HC030031 in similar experimental conditions as in (A) (n = 20 or 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377073&req=5

fig06: The TRPA1 channel blocker HC030031 does not affect oxaliplatin mediated cold hypersensitivity but reverses mechanical hyperalgesiaFilled black circles and bars represent the basal values before oxalipatin injection, while the open circles and bars corresponds to the oxaliplatin (6 mg/kg) treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or vehicle. The red circles/bars and the blue circles/bars represent, respectively, the oxaliplatin–vehicle and the oxaliplatin–HC030031 groups (n = 10 per group). Filled black triangle and grey bars represent the basal values before vehicle injection, while the black open triangle and hatched bars corresponds to the vehicle treated animals at 90 h (n = 20) prior to treatments with HC03031 (100 mg/kg i.p.) or its vehicle. The red triangle/hatched bars and the blue triangles/hatched bars represent, respectively, the vehicle–vehicle and the vehicle–HC030031 groups (n = 10 per group).Lack of effect of TRPA1 channel blockade with acute HC030031 treatment on oxaliplatin cold hyperalgesia (left panel). The same treatment reduces normal cold tolerance in control mice (right panel).Reversal of oxaliplatin-mediated mechanical hyperalgesia by HC030031 in similar experimental conditions as in (A) (n = 20 or 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
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.

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