title: Transient receptor potential ankyrin 1 that is induced in dorsal root ganglion neurons contributes to acute cold hypersensitivity after oxaliplatin administration.
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.
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. k-yamamoto@ac.shoyaku.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. noriko_chiba@med.pref.aomori.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. y12604@toyaku.ac.jp.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Pharmacology, Showa Pharmaceutical University, 3-3165, Machida, Tokyo, 194-8543, Japan. kanbe@ac.shoyaku.ac.jp.
authors.forename: Toshie
authors.initials: T
authors.lastname: Kambe
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima, 963-8611, Japan. k-abe@pha.ohu-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Pharmacy, Cancer Institute Hospital, 3-10-6 Ariake, Koto-ku, Tokyo, 135-8550, Japan. kazu.kawakami@jfcr.or.jp.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Pharmacotheraputics, Showa Pharmaceutical University, 3-3165, Machida, Tokyo, 194-8543, Japan. utsunomi@ac.shoyaku.ac.jp.
authors.forename: Iku
authors.initials: I
authors.lastname: Utsunomiya
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, 194-8543, Japan. taguchi_k@mac.com.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Taguchi
mesh_terms: D000208:Acute Disease; D000818:Animals; D056587:Cryopyrin-Associated Periodic Syndromes / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580