Mechanical antihypersensitivity effect induced by repeated spinal administrations of a TRPA1 antagonist or a gap junction decoupler in peripheral neuropathy

• Published in: Pharmacology, biochemistry and behavior Vol. 150-151; pp. 57 - 67
• Main Authors: Wei, Hong, Wu, Hai-Yun, Chen, Zuyue, Ma, Ai-Niu, Mao, Xiao-Fang, Li, Teng-Fei, Li, Xin-Yan, Wang, Yong-Xiang, Pertovaara, Antti
• Format: Journal Article
• Language: English
• Published: United States 01.11.2016
• Subjects: Amines - pharmacology; Animals; Carbenoxolone - pharmacology; Cyclohexanecarboxylic Acids - pharmacology; D-Amino-Acid Oxidase - genetics; D-Amino-Acid Oxidase - physiology; gamma-Aminobutyric Acid - pharmacology; Gap Junctions - drug effects; Injections, Spinal; Male; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - physiopathology; Rats; TRPA1 Cation Channel; TRPC Cation Channels - antagonists & inhibitors; TRPC Cation Channels - genetics; Gabapentin; TRPA1; Astrocytes; Hydrogen peroxide: Pain; Hypersensitivity; d-Amino acid oxidase; Spinal cord dorsal horn
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2016.09.007

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 H O generated 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.