title: Acrolein contributes to TRPA1 up-regulation in peripheral and central sensory hypersensitivity following spinal cord injury.
abstract: Acrolein, an endogenous aldehyde, has been shown to be involved in sensory hypersensitivity after rat spinal cord injury (SCI), for which the pathogenesis is unclear. Acrolein can directly activate a pro-algesic transient receptor protein ankyrin 1 (TRPA1) channel that exists in sensory neurons. Both acrolein and TRPA1 mRNA are elevated post SCI, which contributes to the activation of TRPA1 by acrolein and consequently, neuropathic pain. In the current study, we further showed that, post-SCI elevation of TRPA1 mRNA exists not only in dorsal root ganglias but also in both peripheral (paw skin) and central endings of primary afferent nerves (dorsal horn of spinal cord). This is the first indication that pain signaling can be over-amplified in the peripheral skin by elevated expressions of TRPA1 following SCI, in addition over-amplification previously seen in the spinal cord and dorsal root ganglia. Furthermore, we show that acrolein alone, in the absence of physical trauma, could lead to the elevation of TRPA1 mRNA at various locations when injected to the spinal cord. In addition, post-SCI elevation of TRPA1 mRNA could be mitigated using acrolein scavengers. Both of these attributes support the critical role of acrolein in elevating TRPA1 expression through gene regulation. Taken together, these data indicate that acrolein is likely a critical causal factor in heightening pain sensation post-SCI, through both the direct binding of TRPA1 receptor, and also by boosting the expression of TRPA1. Finally, our data also further support the notion that acrolein scavenging may be an effective therapeutic approach to alleviate neuropathic pain after SCI. We propose that the trauma-mediated elevation of acrolein causes neuropathic pain through at least two mechanisms: acrolein stimulates the production of transient receptor protein ankyrin 1 (TRPA1) in both central and peripheral locations, and it activates TRPA1 channels directly. Therefore, acrolein appears to be a critical factor in the pathogenesis of post-SCI sensory hypersensitivity, becoming a novel therapeutic target to relieve both acute and chronic post-SCI neuropathic pain.
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jonghyuck
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Lingxing
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Glen
authors.initials: G
authors.lastname: Acosta
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Vega-Alvarez
authors.affiliation: Department of Orthopedics, Rui-Jin Hospital, School of Medicine, Shanghai Jiao-tong University, Institute of Trauma and Orthopedics, Shanghai, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Breanne
authors.initials: B
authors.lastname: Muratori
authors.affiliation: Department of Orthopedics, Rui-Jin Hospital, School of Medicine, Shanghai Jiao-tong University, Institute of Trauma and Orthopedics, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Riyi
authors.initials: R
authors.lastname: Shi
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine; D000171:Acrolein / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006830:Hydralazine / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000150:complications*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D014665:Vasodilator Agents; D006830:Hydralazine; D000171:Acrolein; C001423:S-(3-hydroxypropyl)cysteine N-acetate; D000111:Acetylcysteine
keywords: aldehyde; hydralazine; hyperreflexia; lipid peroxidation; proalgesic