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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

Oxaliplatin increases TRPA1 protein expression as seen with immunohistochemistry in the DRG. a Effect of oxaliplatin (6 mg/kg, i.p.) on co-localization of TRPA1 protein expression with isolectin B4 binding in rat DRG (L4–6) neurons. The photomicrographs show representative data. Co-localization of TRPA1 expression (red) and isolectin B4 binding (green) is shown. Double-labeled neurons (arrowheads) are stained yellow in the merged panel. b Histogram shows the percent of TRPA1-positive neurons relative to isolectin B4-binding neurons. TRPA1 and isolectin B4 co-localization was significantly higher on day 2 after oxaliplatin administration (6 mg/kg, i.p.) compared to 5 % glucose treatment. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration (6 mg/kg, i.p.). *P < 0.05 versus 5 % glucose
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Fig5: Oxaliplatin increases TRPA1 protein expression as seen with immunohistochemistry in the DRG. a Effect of oxaliplatin (6 mg/kg, i.p.) on co-localization of TRPA1 protein expression with isolectin B4 binding in rat DRG (L4–6) neurons. The photomicrographs show representative data. Co-localization of TRPA1 expression (red) and isolectin B4 binding (green) is shown. Double-labeled neurons (arrowheads) are stained yellow in the merged panel. b Histogram shows the percent of TRPA1-positive neurons relative to isolectin B4-binding neurons. TRPA1 and isolectin B4 co-localization was significantly higher on day 2 after oxaliplatin administration (6 mg/kg, i.p.) compared to 5 % glucose treatment. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration (6 mg/kg, i.p.). *P < 0.05 versus 5 % glucose

Mentions: We detected TRPA1 protein expression in DRG (L4–6) neurons at day 2 after oxaliplatin administration using immunohistochemistry. An increase in the frequency of TRPA1-positive cells was found in the oxaliplatin-treated rats compared with 5 % glucose-treated rats (Fig. 5a, b). Using computerized optical density image analysis, we measured the optical density of individual DRG neurons that were TRPA1 positive. Next, we compared isolectin B4-binding small neurons (green in Fig. 5a) between oxaliplatin- and 5 % glucose-treated rats. TRPA1 expression (red in Fig. 5a) overlapped with isolectin B4 binding to neurons. Immunofluorescence double-labeling experiments revealed a pronounced overlap between small-diameter DRG neurons expressing TRPA1 and isolectin B4 binding (yellow in Fig. 5a, merged). In 5 % glucose-treated rats, approximately half of the isolectin B4-binding DRG neurons were immunostained for TRPA1. The percent of TRPA1/isolectin B4 dual-positive cells relative to the total isolectin B4-binding neurons was significantly increased at day 2 after oxaliplatin administration (45.8 ± 5.0 vs. 64.7 ± 3.9 %, P < 0.05, n = 4) (Fig. 5b). Thus, oxaliplatin significantly increased expression of TRPA1 and isolectin B4 binding in DRG neurons.Fig. 5


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 increases TRPA1 protein expression as seen with immunohistochemistry in the DRG. a Effect of oxaliplatin (6 mg/kg, i.p.) on co-localization of TRPA1 protein expression with isolectin B4 binding in rat DRG (L4–6) neurons. The photomicrographs show representative data. Co-localization of TRPA1 expression (red) and isolectin B4 binding (green) is shown. Double-labeled neurons (arrowheads) are stained yellow in the merged panel. b Histogram shows the percent of TRPA1-positive neurons relative to isolectin B4-binding neurons. TRPA1 and isolectin B4 co-localization was significantly higher on day 2 after oxaliplatin administration (6 mg/kg, i.p.) compared to 5 % glucose treatment. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration (6 mg/kg, i.p.). *P < 0.05 versus 5 % glucose
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Fig5: Oxaliplatin increases TRPA1 protein expression as seen with immunohistochemistry in the DRG. a Effect of oxaliplatin (6 mg/kg, i.p.) on co-localization of TRPA1 protein expression with isolectin B4 binding in rat DRG (L4–6) neurons. The photomicrographs show representative data. Co-localization of TRPA1 expression (red) and isolectin B4 binding (green) is shown. Double-labeled neurons (arrowheads) are stained yellow in the merged panel. b Histogram shows the percent of TRPA1-positive neurons relative to isolectin B4-binding neurons. TRPA1 and isolectin B4 co-localization was significantly higher on day 2 after oxaliplatin administration (6 mg/kg, i.p.) compared to 5 % glucose treatment. Data are the mean ± SEM. n = 4 each for 5 % glucose and oxaliplatin administration (6 mg/kg, i.p.). *P < 0.05 versus 5 % glucose
Mentions: We detected TRPA1 protein expression in DRG (L4–6) neurons at day 2 after oxaliplatin administration using immunohistochemistry. An increase in the frequency of TRPA1-positive cells was found in the oxaliplatin-treated rats compared with 5 % glucose-treated rats (Fig. 5a, b). Using computerized optical density image analysis, we measured the optical density of individual DRG neurons that were TRPA1 positive. Next, we compared isolectin B4-binding small neurons (green in Fig. 5a) between oxaliplatin- and 5 % glucose-treated rats. TRPA1 expression (red in Fig. 5a) overlapped with isolectin B4 binding to neurons. Immunofluorescence double-labeling experiments revealed a pronounced overlap between small-diameter DRG neurons expressing TRPA1 and isolectin B4 binding (yellow in Fig. 5a, merged). In 5 % glucose-treated rats, approximately half of the isolectin B4-binding DRG neurons were immunostained for TRPA1. The percent of TRPA1/isolectin B4 dual-positive cells relative to the total isolectin B4-binding neurons was significantly increased at day 2 after oxaliplatin administration (45.8 ± 5.0 vs. 64.7 ± 3.9 %, P < 0.05, n = 4) (Fig. 5b). Thus, oxaliplatin significantly increased expression of TRPA1 and isolectin B4 binding in DRG neurons.Fig. 5

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