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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.


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Oxaliplatin administration increases TRPA1 mRNA and protein in DRGs. a Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 mRNA expression in rat DRGs (L4–6) at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 mRNA in oxaliplatin-treated rats compared with day 0. Data are the mean ± SEM. n = 4 for oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0. b Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 protein expression in rat DRGs (L4–6). TRPA1 and β-actin protein in DRGs at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 protein in oxaliplatin-treated rats. The western blot shows representative data. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0
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Fig2: Oxaliplatin administration increases TRPA1 mRNA and protein in DRGs. a Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 mRNA expression in rat DRGs (L4–6) at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 mRNA in oxaliplatin-treated rats compared with day 0. Data are the mean ± SEM. n = 4 for oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0. b Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 protein expression in rat DRGs (L4–6). TRPA1 and β-actin protein in DRGs at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 protein in oxaliplatin-treated rats. The western blot shows representative data. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0

Mentions: We investigated the expression of TRPA1 mRNA during acute cold hypersensitivity after oxaliplatin administration. We removed DRGs (L4–6) at days 1, 2, 4, and 7 after the start of 6 mg/kg oxaliplatin, and TRPA1 mRNA expression was quantified with RT-PCR. As shown in Fig. 2a, 6 mg/kg oxaliplatin significantly increased TRPA1 mRNA expression in DRGs at days 1 (127.9 ± 10.4 %, n = 4, P < 0.01), 2 (125.1 ± 10.8 %, n = 4, P < 0.01), and 4 (114.9 ± 7.3 %, n = 4, P < 0.05) compared to day 0 (100.0 ± 6.3 %). TRPA1 mRNA expression was maximally increased at day 1 and returned to control levels 7 days after administration of oxaliplatin (Fig. 2a).Fig. 2


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)

Oxaliplatin administration increases TRPA1 mRNA and protein in DRGs. a Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 mRNA expression in rat DRGs (L4–6) at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 mRNA in oxaliplatin-treated rats compared with day 0. Data are the mean ± SEM. n = 4 for oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0. b Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 protein expression in rat DRGs (L4–6). TRPA1 and β-actin protein in DRGs at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 protein in oxaliplatin-treated rats. The western blot shows representative data. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0
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Fig2: Oxaliplatin administration increases TRPA1 mRNA and protein in DRGs. a Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 mRNA expression in rat DRGs (L4–6) at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 mRNA in oxaliplatin-treated rats compared with day 0. Data are the mean ± SEM. n = 4 for oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0. b Effect of oxaliplatin (6 mg/kg, i.p.) on TRPA1 protein expression in rat DRGs (L4–6). TRPA1 and β-actin protein in DRGs at days 0 (before administration), 1, 2, 4, and 7 was measured. TRPA1 expression was normalized to β-actin expression. Histograms show the relative amount of TRPA1 protein in oxaliplatin-treated rats. The western blot shows representative data. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration. *P < 0.05, **P < 0.01 versus day 0
Mentions: We investigated the expression of TRPA1 mRNA during acute cold hypersensitivity after oxaliplatin administration. We removed DRGs (L4–6) at days 1, 2, 4, and 7 after the start of 6 mg/kg oxaliplatin, and TRPA1 mRNA expression was quantified with RT-PCR. As shown in Fig. 2a, 6 mg/kg oxaliplatin significantly increased TRPA1 mRNA expression in DRGs at days 1 (127.9 ± 10.4 %, n = 4, P < 0.01), 2 (125.1 ± 10.8 %, n = 4, P < 0.01), and 4 (114.9 ± 7.3 %, n = 4, P < 0.05) compared to day 0 (100.0 ± 6.3 %). TRPA1 mRNA expression was maximally increased at day 1 and returned to control levels 7 days after administration of oxaliplatin (Fig. 2a).Fig. 2

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