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Transient receptor potential ankyrin 1 that is induced in dorsal root ganglion neurons contributes to acute cold hypersensitivity after oxaliplatin administration.

Yamamoto K, Chiba N, Chiba T, Kambe T, Abe K, Kawakami K, Utsunomiya I, Taguchi K - Mol Pain (2015)

Bottom Line: Oxaliplatin significantly increased co-localization of TRPA1 expression and isolectin B4 binding in DRG neurons.In addition, we found that intrathecal administration of TRPA1 antisense, but not TRPA1 mismatched oligodeoxynucleotides, knocked down TRPA1 expression and decreased oxaliplatin-induced cold hyperalgesia.Intrathecal administration of the p38 MAPK inhibitor, SB203580, significantly decreased oxaliplatin-induced acute cold hypersensitivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. k-yamamoto@ac.shoyaku.ac.jp.

ABSTRACT

Background: Peripheral cold neuropathic pain is a serious side effect of oxaliplatin treatment. However, the mechanism of oxaliplatin-induced cold hyperalgesia is unknown. In the present study, we investigated the effects of oxaliplatin on transient receptor potential ankyrin 1 (TRPA1) in dorsal root ganglion (DRG) neurons of rats.

Results: Behavioral assessment using the acetone spray test showed that 3 and 6 mg/kg oxaliplatin (i.p.) induced acute cold hypersensitivity after 1, 2, 4, and 7 days. Real-time PCR showed that oxaliplatin (6 mg/kg) significantly increased TRPA1 mRNA expression in DRGs at days 1, 2, and 4. Western blotting revealed that oxaliplatin significantly increased TRPA1 protein expression in DRGs at days 2, 4, and 7. Moreover, in situ hybridization histochemistry revealed that most TRPA1 mRNA-labeled neurons in the DRGs were small in size. Oxaliplatin significantly increased co-localization of TRPA1 expression and isolectin B4 binding in DRG neurons. Oxaliplatin induced a significant increase in the percent of TRPA1 mRNA-positive small neurons in DRGs at days 1, 2, and 4. In addition, we found that intrathecal administration of TRPA1 antisense, but not TRPA1 mismatched oligodeoxynucleotides, knocked down TRPA1 expression and decreased oxaliplatin-induced cold hyperalgesia. Double labeling showed that p-p38 mitogen-activated protein kinase (MAPK) was co-expressed in TRPA1 mRNA-labeled neurons at day 2 after oxaliplatin administration. Intrathecal administration of the p38 MAPK inhibitor, SB203580, significantly decreased oxaliplatin-induced acute cold hypersensitivity.

Conclusions: Together, these results demonstrate that TRPA1 expression via activation of p38 MAPK in DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia.

No MeSH data available.


Related in: MedlinePlus

Time course of acute cold hypersensitivity after oxaliplatin administration. The acetone spray test was used to measure cold response (1, 3, and 6 mg/kg, i.p.) in rats at days 1–7 after oxaliplatin administration. Data are the mean ± SEM of n = 8–10 rats. *P < 0.05, **P < 0.01, two-way ANOVA with Dunnett’s post hoc analysis compared to control (5 % glucose)
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Fig1: Time course of acute cold hypersensitivity after oxaliplatin administration. The acetone spray test was used to measure cold response (1, 3, and 6 mg/kg, i.p.) in rats at days 1–7 after oxaliplatin administration. Data are the mean ± SEM of n = 8–10 rats. *P < 0.05, **P < 0.01, two-way ANOVA with Dunnett’s post hoc analysis compared to control (5 % glucose)

Mentions: We first investigated the effect of oxaliplatin (1, 3, and 6 mg/kg, i.p.) on acute cold hypersensitivity. Before the first single dose of oxaliplatin, we found no significant differences in the number of withdrawal responses in any groups in the acetone spray test. Oxaliplatin (1 mg/kg, i.p.) did not affect the paw withdrawal response rate in the acetone spray test. However, the response rate was significantly increased with 3 and 6 mg/kg oxaliplatin in the acetone spray test at days 1–7 after a single dose of oxaliplatin compared to 5 % glucose treatment (Fig. 1).Fig. 1


Transient receptor potential ankyrin 1 that is induced in dorsal root ganglion neurons contributes to acute cold hypersensitivity after oxaliplatin administration.

Yamamoto K, Chiba N, Chiba T, Kambe T, Abe K, Kawakami K, Utsunomiya I, Taguchi K - Mol Pain (2015)

Time course of acute cold hypersensitivity after oxaliplatin administration. The acetone spray test was used to measure cold response (1, 3, and 6 mg/kg, i.p.) in rats at days 1–7 after oxaliplatin administration. Data are the mean ± SEM of n = 8–10 rats. *P < 0.05, **P < 0.01, two-way ANOVA with Dunnett’s post hoc analysis compared to control (5 % glucose)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644342&req=5

Fig1: Time course of acute cold hypersensitivity after oxaliplatin administration. The acetone spray test was used to measure cold response (1, 3, and 6 mg/kg, i.p.) in rats at days 1–7 after oxaliplatin administration. Data are the mean ± SEM of n = 8–10 rats. *P < 0.05, **P < 0.01, two-way ANOVA with Dunnett’s post hoc analysis compared to control (5 % glucose)
Mentions: We first investigated the effect of oxaliplatin (1, 3, and 6 mg/kg, i.p.) on acute cold hypersensitivity. Before the first single dose of oxaliplatin, we found no significant differences in the number of withdrawal responses in any groups in the acetone spray test. Oxaliplatin (1 mg/kg, i.p.) did not affect the paw withdrawal response rate in the acetone spray test. However, the response rate was significantly increased with 3 and 6 mg/kg oxaliplatin in the acetone spray test at days 1–7 after a single dose of oxaliplatin compared to 5 % glucose treatment (Fig. 1).Fig. 1

Bottom Line: Oxaliplatin significantly increased co-localization of TRPA1 expression and isolectin B4 binding in DRG neurons.In addition, we found that intrathecal administration of TRPA1 antisense, but not TRPA1 mismatched oligodeoxynucleotides, knocked down TRPA1 expression and decreased oxaliplatin-induced cold hyperalgesia.Intrathecal administration of the p38 MAPK inhibitor, SB203580, significantly decreased oxaliplatin-induced acute cold hypersensitivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. k-yamamoto@ac.shoyaku.ac.jp.

ABSTRACT

Background: Peripheral cold neuropathic pain is a serious side effect of oxaliplatin treatment. However, the mechanism of oxaliplatin-induced cold hyperalgesia is unknown. In the present study, we investigated the effects of oxaliplatin on transient receptor potential ankyrin 1 (TRPA1) in dorsal root ganglion (DRG) neurons of rats.

Results: Behavioral assessment using the acetone spray test showed that 3 and 6 mg/kg oxaliplatin (i.p.) induced acute cold hypersensitivity after 1, 2, 4, and 7 days. Real-time PCR showed that oxaliplatin (6 mg/kg) significantly increased TRPA1 mRNA expression in DRGs at days 1, 2, and 4. Western blotting revealed that oxaliplatin significantly increased TRPA1 protein expression in DRGs at days 2, 4, and 7. Moreover, in situ hybridization histochemistry revealed that most TRPA1 mRNA-labeled neurons in the DRGs were small in size. Oxaliplatin significantly increased co-localization of TRPA1 expression and isolectin B4 binding in DRG neurons. Oxaliplatin induced a significant increase in the percent of TRPA1 mRNA-positive small neurons in DRGs at days 1, 2, and 4. In addition, we found that intrathecal administration of TRPA1 antisense, but not TRPA1 mismatched oligodeoxynucleotides, knocked down TRPA1 expression and decreased oxaliplatin-induced cold hyperalgesia. Double labeling showed that p-p38 mitogen-activated protein kinase (MAPK) was co-expressed in TRPA1 mRNA-labeled neurons at day 2 after oxaliplatin administration. Intrathecal administration of the p38 MAPK inhibitor, SB203580, significantly decreased oxaliplatin-induced acute cold hypersensitivity.

Conclusions: Together, these results demonstrate that TRPA1 expression via activation of p38 MAPK in DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia.

No MeSH data available.


Related in: MedlinePlus