title: Potential role of spinal TRPA1 channels in antinociceptive tolerance to spinally administered morphine.
abstract: BACKGROUND
  Prolonged morphine treatment leads to antinociceptive tolerance. Suppression of spinal astrocytes or d-amino acid oxidase (DAAO), an astroglial enzyme catalyzing oxidation of d-amino acids, has reversed morphine antinociceptive tolerance. Since the astrocyte-DAAO pathway generates hydrogen peroxide, an agonist of the TRPA1 channel expressed spinally on nociceptive nerve terminals and astrocytes, we tested a hypothesis that the spinal TRPA1 contributes to antinociceptive tolerance to prolonged spinal morphine treatment.
  
  
  METHODS
  Nociception was assessed using hot-plate test in rats with an intrathecal (it) catheter. Drugs were administered it twice daily from day one to seven in five treatment groups: (i) Saline, (ii) Chembridge-5861528 (a TRPA1 antagonist; 10μg), (iii) morphine (10μg), (iv) Chembridge-5861528 (10μg)+morphine (10μg), (v) DMSO. Antinociceptive action of morphine was assessed at day one and eight. Additionally, mRNA for DAAO and TRPA1 in the spinal cord was determined on day 8.
  
  
  RESULTS
  Morphine treatment produced antinociceptive tolerance, which was attenuated by co-administration of Chembridge-5861528 that alone had no effect on hot-plate latencies. In animals treated with morphine only, spinal mRNA for DAAO but not TRPA1 was increased. DAAO increase was prevented by co-administration of Chembridge-5861528.
  
  
  CONCLUSIONS
  Antinociceptive morphine tolerance and up-regulation of spinal DAAO were attenuated in morphine-treated animals by blocking the spinal TRPA1. This finding suggests that spinal TRPA1 may contribute, at least partly, to facilitation of morphine antinociceptive tolerance through mechanisms that possibly involve TRPA1-mediated up-regulation of the astroglial DAAO, a generator of hydrogen peroxide, a pronociceptive compound acting also on TRPA1.
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wu
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Li
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ai-Niu
authors.initials: AN
authors.lastname: Ma
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: antti.pertovaara@helsinki.fi.
authors.forename: Antti
authors.initials: A
authors.lastname: Pertovaara
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D012333:RNA, Messenger; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D009020:Morphine; D003605:D-Amino-Acid Oxidase
keywords: Heat pain behavior; Opioid antinociceptive tolerance; Spinal dorsal horn; Transient receptor potential ankyrin 1