Mechanical antihypersensitivity effect induced by repeated spinal administrations of a TRPA1 antagonist or a gap junction decoupler in peripheral neuropathy.
Spinal transient receptor potential ankyrin 1 (TRPA1) channel is associated with various pain hypersensitivity conditions. Spinally, TRPA1 is expressed by central terminals of nociceptive nerve fibers and astrocytes. Among potential endogenous agonists of TRPA1 is H2O2generated by d-amino acid oxidase (DAAO) in astrocytes. Here we studied whether prolonged block of the spinal TRPA1 or astrocytes starting at time of injury attenuates development and/or maintenance of neuropathic hypersensitivity. Additionally, TRPA1 and DAAO mRNA were determined in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH). Experiments were performed in rats with spared nerve injury (SNI) and chronic intrathecal catheter. Drugs were administered twice daily for the first seven injury days or only once seven days after injury. Mechanical hypersensitivity was assessed with monofilaments. Acute and prolonged treatment with Chembridge-5861528 (a TRPA1 antagonist), carbenoxolone (an inhibitor of activated astrocytes), or gabapentin (a comparison drug) attenuated tactile allodynia-like responses evoked by low (2g) stimulus. However, antihypersensitivity effect of these compounds was short of significance at a high (15g) stimulus intensity. No preemptive effects were observed. In healthy controls, carbenoxolone failed to prevent hypersensitivity induced by spinal cinnamaldehyde, a TRPA1 agonist. TRPA1 and DAAO mRNA in the DRG but not SDH were slightly increased in SNI, independent of drug treatment. The results indicate that prolonged peri-injury block of spinal TRPA1 or inhibition of spinal astrocyte activation attenuates maintenance but not development of mechanical (tactile allodynia-like) hypersensitivity after nerve injury.
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Hong
H
Wei
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Hai-Yun
HY
Wu
Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Aalto 00076, Finland.
Zuyue
Z
Chen
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Ai-Niu
AN
Ma
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Xiao-Fang
XF
Mao
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Teng-Fei
TF
Li
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Xin-Yan
XY
Li
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. Electronic address: yxwang@sjtu.edu.cn.
Yong-Xiang
YX
Wang
Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: antti.pertovaara@helsinki.fi.
Antti
A
Pertovaara
D000588:Amines / Q000494:pharmacology; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000502:physiology; D000077206:Gabapentin; D017629:Gap Junctions / Q000187:drug effects*; D007278:Injections, Spinal; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D003605:D-Amino-Acid Oxidase; D002229:Carbenoxolone
Astrocytes; Gabapentin; Hydrogen peroxide: Pain; Hypersensitivity; Spinal cord dorsal horn; TRPA1; d-Amino acid oxidase